相关申请的交叉引用
本申请要求于2017年8月1日提交的题为“用于对样品执行实时测定的系统和方法(systemsandmethodsforperformingareal-timeassayofasample)”的美国临时专利申请号62/539,803的优先权,其全部公开内容通过引用并入本文。
本披露总体上涉及测定,并且更具体地,涉及对样品执行实时测定。
序列表
本申请连同电子格式的序列表一起提交。序列表作为名为“51800_seqlisting.txt”的文件提供,所述文件创建于2018年7月31日,大小为263,964字节。将电子格式的序列表的信息通过引用以其全文并入本文。
背景技术:
测定通常用于量化分析物(如药物、生化物质、或细胞)的一个或多个属性。这种测定的一个实例是多属性方法(mam)测定,其可以检测和量化样品的关键质量属性(cqa),所述关键质量属性由质量目标产物概况(qtpp)鉴别(developmentofaquantitativemassspectrometrymulti-attributemethodforcharacterization,qualitycontroltestinganddispositionofbiologics[用于生物制剂的表征、质量控制测试和处置的定量质谱多属性方法的开发].rogersrs,nightlingerns,livingstonb,campbellp,baileyr,ballanda.mabs.2015;7(5):881-90)。所述mam测定是在例如大分子释放测试(lmrt)实验室中进行的手动操作过程。mam是基于液相色谱(lc)-质谱(ms)的肽作图方法,包括三个步骤:(1)样品制备(例如多肽变性、还原、烷基化和消化);(2)通过lc分离消化的多肽并通过ms检测;和(3)与参考标准相比,分析目标cqa的数据并检测新信号(即峰值)。
cqa是在特定值或范围值内存在的化学、物理或生物学特性。例如,对于大的多肽治疗分子,氨基酸(多肽的构建模块)的物理属性和修饰是在制造过程中、制造后、以及在药物开发过程中监测的重要cqa。与跟踪整个多肽或部分多肽的峰大小和峰形状变化的常规分析测定不同,mam在氨基酸水平检测特定的cqa。
然而,尽管mam是在开发、制造和储存过程中评估多肽治疗性分子cqa的重要进展(评估,例如稳定性),但从样品制备到最终分析,分析可能需要七到十天的时间,这会增加成本并延迟开发和药物释放。例如,多肽治疗剂通常由表达靶多肽的培养细胞产生。在cqa的mam分析等待时,这种生产系统不容易“搁置”,导致细胞产生具有不符合规格的cqa的靶多肽——浪费时间、材料和人力。此外,在药物开发过程中,例如,在优化培养条件时,会累积七到十天的延迟,这阻碍向患者提供重要的新多肽药物。因此,需要有效且更快的方法来促进使用mam的cqa分析。
技术实现要素:
本披露的一个方面提供了一种用于执行实时测定的方法。所述方法包括以下步骤:(a)将含有多肽的产物的样品经由第一保持盘管移动至多肽结合柱;(b)将所述样品中的所述多肽结合至所述多肽结合柱,从而将所述样品中的所述多肽与所述样品的其余部分分离;(c)将洗脱缓冲溶液经由所述第一保持盘管并通过所述多肽结合柱下游的第二保持盘管从缓冲液源移动至所述多肽结合柱,从而洗脱与所述多肽结合柱结合的多肽,并将包含所述洗脱缓冲溶液和洗脱的多肽的洗脱液/多肽混合物移动至所述第二保持盘管;(d)将所述洗脱液/多肽混合物从所述第二保持盘管移动至反应室;(e)将所述洗脱液/多肽混合物中的所述多肽在所述反应室中进行孵育,从而产生变性的多肽;(f)在(e)之后,将切割二硫键交联的还原试剂经由第一保持盘管移动至所述反应室;(g)将所述变性的多肽与所述还原试剂在所述反应室中进行孵育,从而产生变性和还原的多肽;(h)在(g)之后,将使巯基烷基化的烷基化试剂移动至所述反应室;(i)将所述变性和还原的多肽与所述烷基化试剂在所述反应室中进行孵育,从而使所述变性和还原的多肽烷基化;(j)将所述变性、还原并烷基化的多肽,所述洗脱缓冲溶液,所述还原试剂和所述烷基化试剂经由所述第一保持盘管从所述反应室移动至脱盐柱,所述脱盐柱用蛋白质水解缓冲液平衡;(k)将所述变性、还原并烷基化的多肽应用至所述脱盐柱,从而将所述变性、还原并烷基化的多肽与所述还原试剂和烷基化试剂分离,从而得到脱盐的多肽;(l)将所述脱盐的多肽移动至所述脱盐柱下游的蛋白水解酶柱;(m)在第三多肽柱中消化所述脱盐的多肽,从而产生消化的多肽;以及(n)将所述消化的多肽移动至分析装置以分析所述消化的多肽。
本披露的另一方面提供了一种用于使用封闭系统执行实时测定的方法,所述封闭系统包括多通路阀、在所述多通路阀上游的第一保持盘管、与所述多通路阀的第一通路流体地联接并位于其下游的多肽结合柱、与所述多肽结合柱流体地联接并位于其下游的第二保持盘管、与所述多通路阀的第二和第三通路流体地联接并位于其下游的反应室、与所述多通路阀的第四通路流体地联接并位于其下游的脱盐柱,以及在所述脱盐柱下游的蛋白水解酶柱。所述方法包括:(a)经由与所述封闭系统通信地联接的控制器,将含有多肽的产物的样品移动至所述第一保持盘管;(b)经由所述控制器将所述多通路阀定位在第一位置,在所述第一位置中,所述第一保持盘管经由所述多通路阀的所述第一通路连接至所述多肽结合柱,使得所述样品流动至第一柱,从而所述样品中的多肽结合至所述多肽结合柱上;(c)当所述多通路阀处于所述第一位置时,经由控制器将洗脱缓冲溶液从洗脱缓冲溶液源经由所述多肽结合柱移动至所述第二保持盘管,使得所述洗脱缓冲溶液洗脱基本上所有与所述多肽结合柱结合的多肽;(d)经由所述控制器将所述多通路阀移动至第二位置,在所述第二位置中,所述第二保持盘管经由所述多通路阀的所述第二通路连接至所述反应室;(e)当所述多通路阀处于所述第二位置时,经由所述控制器将包含所述洗脱缓冲溶液和洗脱的多肽的洗脱液/多肽混合物移动至所述反应室,从而使所述洗脱液/多肽混合物中的多肽变性;(f)经由所述控制器将多通路阀移动至第三位置,在所述第三位置中,所述第一保持盘管经由所述多通路阀的所述第三通路连接至所述反应室;(g)在(f)之后,经由所述控制器将切割二硫键交联的还原试剂移动至所述第一保持盘管,并且经由所述控制器将所述还原试剂从所述第一保持盘管经由所述多通路阀的所述第三通路移动至所述反应室,从而还原所述变性的多肽;(h)在(g)之后,经由所述控制器将使巯基烷基化的烷基化试剂移动至所述第一保持盘管,并且经由所述控制器将所述烷基化试剂从所述第一保持盘管经由所述第三通路移动至所述反应室,从而烷基化所述变性和还原的多肽;(i)经由所述控制器将所述烷基化的多肽、所述洗脱缓冲溶液、所述还原试剂和所述烷基化试剂从所述反应室经由所述第三通路移动至所述第一保持盘管;(j)经由所述控制器将所述多通路阀移动至第四位置,在所述第四位置中,所述第一保持盘管经由所述多通路阀的第四通路连接至所述脱盐柱,并且当所述多通路阀处于在所述第四位置时,将所述烷基化的多肽、所述洗脱缓冲溶液、所述还原试剂和所述烷基化试剂从所述第一保持盘管移动至所述脱盐柱,从而将所述变性、还原并烷基化的多肽应用至所述脱盐柱,由此将所述变性、还原并烷基化的多肽与所述还原试剂和烷基化试剂分离,得到脱盐的多肽;(k)经由所述控制器将所述脱盐的多肽移动至所述蛋白水解酶柱,从而消化所述脱盐的多肽;以及(l)经由所述控制器将所述消化的多肽传送至分析装置,从而分析所述消化的多肽。
本披露的另一方面提供了用于执行联机、实时测定的封闭系统。所述系统包括:第一保持盘管,所述第一保持盘管流体地布置成接收含有多肽的产物的样品;多通路阀,所述多通路阀流体地联接至所述第一保持盘管并位于其下游;多肽结合柱,所述多肽结合柱流体地联接至所述多通路阀,并布置成经由所述多通路阀的第一通路从所述第一保持盘管接收所述样品,所述多肽结合柱被配置为结合来自所述样品的所述多肽;缓冲液源,所述缓冲液源流体地联接至所述多通路阀,并被布置成向位于所述多肽结合柱下游的第二保持盘管供应洗脱缓冲溶液,使得所述洗脱缓冲溶液适于从所述多肽结合柱上洗脱基本上所有的所述多肽;反应室,所述反应室流体地联接至所述多通路阀并被布置在所述多肽结合柱下游,所述反应室适于经由所述多通路阀的第二通路从所述多肽结合柱接收混合物,所述混合物包含所述洗脱缓冲溶液和所述洗脱的多肽,其中所述混合物的多肽在所述反应室中变性,其中所述反应室被布置成经由所述多通路阀的第一保持盘管和第三通路接收切割二硫键交联的还原试剂,所述还原试剂还原所述变性的多肽,并且其中所述反应室还被布置成经由所述多通路阀的第一保持盘管和第三通路接收使巯基烷基化的烷基化试剂,其中所述烷基化试剂在所述反应室中将所述变性并还原的多肽烷基化;脱盐柱,所述脱盐柱流体地联接至所述多通路阀,并且被布置成从所述反应室接收变性、还原并烷基化的多肽,所述洗脱缓冲溶液和所述烷基化试剂,所述脱盐柱被配置为将所述变性、还原并烷基化的多肽与所述洗脱缓冲溶液、所述还原试剂和所述烷基化试剂分离;以及蛋白水解酶柱,所述蛋白水解酶柱流体地联接至第二多肽柱并被布置成在其下游以从所述脱盐柱获得所述分离的多肽,所述蛋白水解酶柱被配置为消化脱盐的多肽。
本披露的另一方面提供了用于执行实时测定的封闭系统。所述系统包括:多通路阀;第一保持盘管,所述第一保持盘管在所述多通路阀上游;多肽结合柱,所述多肽结合柱流体地联接至所述多通路阀的第一通路并在其下游;第二保持盘管,所述第二保持盘管流体地联接至所述多肽结合柱并在其下游;反应室,所述反应室流体地联接至所述多通路阀的第二和第三通路并在其下游;脱盐柱,所述脱盐柱流体地联接至所述多通路阀的第四通路并在其下游;蛋白水解酶柱,所述蛋白水解酶柱位于所述脱盐柱下游;以及控制器,所述控制器通信地联接至所述多通路阀。所述控制器包括存储器、处理器以及逻辑,所述逻辑存储在所述存储器上并且可由所述处理器执行以:(a)将含有多肽的产物的样品移动至所述第一保持盘管;(b)将所述多通路阀定位在第一位置,在所述第一位置中,所述第一保持盘管经由所述多通路阀的所述第一通路连接至所述多肽结合柱,使得所述样品流动至第一柱,从而所述样品中的多肽结合至所述多肽结合柱上;(c)当所述多通路阀处于所述第一位置时,将洗脱缓冲溶液从洗脱缓冲溶液源经由所述多肽结合柱移动至所述第二保持盘管,使得所述洗脱缓冲溶液洗脱基本上所有与所述多肽结合柱结合的所述多肽;(d)将所述多通路阀移动至第二位置,在所述第二位置中,所述第二保持盘管经由所述多通路阀的所述第二通路连接至所述反应室;(e)当所述多通路阀处于所述第二位置时,将包含所述洗脱缓冲溶液和洗脱的多肽的洗脱液/多肽混合物移动至所述反应室,从而将所述洗脱液/多肽混合物中的所述多肽变性;(f)将所述多通路阀移动至第三位置,在所述第三位置中,所述第一保持盘管经由所述多通路阀的所述第三通路连接至所述反应室;(g)在(f)之后,将切割二硫键的还原试剂移动至所述第一保持盘管,并且将所述还原试剂从所述第一保持盘管经由所述多通路阀的所述第三通路移动至所述反应室,从而还原所述变性的多肽;(h)在(g)之后,将使巯基烷基化的烷基化试剂移动至所述第一保持盘管,并且将所述烷基化试剂从所述第一保持盘管经由所述第三通路移动至所述反应室,从而烷基化所述变性并还原的多肽;(i)将所述变性、还原并烷基化的多肽,所述洗脱缓冲溶液,所述还原试剂和所述烷基化试剂从所述反应室经由所述第三通路移动至所述第一保持盘管;(j)将所述多通路阀移动至第四位置,在所述第四位置中,所述第一保持盘管经由所述多通路阀的所述第四通路连接至所述脱盐柱,并且当所述多通路阀处于所述第四位置时,将所述变性、还原并烷基化的多肽,所述洗脱缓冲溶液,所述还原试剂和所述烷基化试剂从所述第一保持盘管移动至所述脱盐柱,从而使所述变性、还原并烷基化的多肽脱盐;(k)将所述脱盐的多肽移动至所述蛋白水解酶柱,从而消化所述脱盐的多肽;以及(l)将所述消化的多肽传送至聚糖分析装置,从而分离并量化所述消化的多肽。
附图说明
图1是根据本披露的教导组装的用于执行联机、实时测定的系统的示意图。
图2是图1所示系统的控制器的示意图。
图3a和图3b是描绘在40天的生产运行期间监测图1系统的有效性的研究的结果图。
图3c是描绘8天期间图3b的结果的快照的图。
具体实施方式
本披露提供了允许实时监测和控制cqa的实时测定和方法,从而可以产生所需的最终多肽治疗产物。披露的测定和方法可以促进mam结果的周转时间,使得结果可以在若干小时(例如,两到三小时)内获得,而不是通常的手动操作的七到十天的离线测量结果。因此,所披露的测定和方法将周转时间提高了约54倍至120倍。这样的“即时”(实时)结果可以调整生产变量,以有效地生产具有适当cqa的(联机)产物。
图1示出了根据本披露的教导组装的系统100的示意图。可以位于实验室(例如,大分子释放测试实验室)处或内的系统100是封闭系统,用于自动或基本上自动地对包含多肽的产物的样品进行测定,如下面更详细地描述。通过使用系统100使该过程自动化(或基本自动化),可以实时(或基本实时)执行测定,从而整个过程可以小时计(例如2到3小时)地进行,并获得所需结果,这比常规上已知的手动操作的mam分析通常需要的7到10天有显著改善。此外,利用系统100的过程的封闭性质维持无菌条件。
在该版本中,多肽可以是治疗性多肽,其在下面将进一步讨论
图1所示的系统100通常包括:多通路阀104、第一保持盘管108、第一柱112、第二保持盘管116、反应室120、第二柱124、第三柱128和控制器132。在图1所示的版本中,系统100还包括容器136、泵140、第一废物室144、第二废物室148、第三废物室152和用于分析多肽的分析装置156。然而,在其他版本中,系统100不能包括这些组件中的一个或多个。作为实例,系统100不能包括容器136和/或分析装置156。在任何情况下,通常常规的管道系统在系统100的每个组件之间延伸,以便在需要时促进系统100的组件之间的流体连通,这将在下面更详细地描述。多通路阀104通常被配置为控制系统100的各个部件之间的流体连通。在该版本中,多通路阀104是十二个卫星通路和中心共享通路阀。换句话说,多通路阀104具有中心通路160和十二个卫星通路164-175,其选择性地流体地联接至中心通路160。多通路阀104可在十二个不同的位置之间移动,所述十二个不同的位置分别将中心通路160与十二个不同的卫星通路164-175流体联接(其中一些未在图1的系统100的运行中使用)。在其他版本中,多通路阀104可以包括更多或更少的卫星通路,可以是不同类型的阀,或者可以被一个或多个不同的阀(每个具有一个或多个通路)代替。作为示例,多通路阀104可以由分别连接到控制器132并由其控制的多个单通路阀代替,其中每个单通阀有效地代替了卫星通路164-175之一。
容器136通常被配置为容纳或存储含有待测定的多肽的产物。该版本的容器136采用容纳或存储产物的生物反应器的形式。然而,在其他版本中,容器136可以替代地采取细胞培养容器的形式,例如烧瓶,平板等。容器136经由管道系统的导管180流体地联接至阀104的卫星通路164,使得当需要时,阀104可以从容器136获得容器136中包含的产物的样品。
第一保持盘管108位于阀104的上游,并通过管道系统的导管184流体地联接至阀104的中心通路160。因此,当阀104处于第一位置(在所述第一位置,中心通路160流体地联接至卫星通路164)时,第一保持盘管108被布置为经由阀104接收来自容器136的产物的样品。
第一柱112位于阀104的下游,并且通过管道系统的导管188流体地联接至阀104的卫星通路165。因此,当阀104处于第二位置(在所述第二位置,中心通路160流体地联接至卫星通路165)时,第一柱112被布置为经由阀104接收来自第一保持盘管108的样品。当第一柱112接收样品时,第一柱112被配置为在样品流过时结合来自样品的多肽。以此方式,第一柱112将样品中的多肽与样品的其余部分分开,所述其余部分可经由第二保持盘管116传送至第一废物室144。
第一柱112,在本文中也可以称为多肽结合柱,选自由以下组成的组:蛋白a柱、蛋白g柱、蛋白a/g柱、蛋白l柱、氨基酸柱、亲和素柱、链霉亲和素柱、碳水化合物结合柱、碳水化合物柱、谷胱甘肽柱、肝素柱、疏水相互作用柱、免疫亲和柱、核苷酸/辅酶柱、专门柱和固定化金属亲和色谱(imac)柱。例如,在多肽是1、2或4亚类的人iggigm、iga或ige(并包含人vh3家族的人fc部分和/或fab区)的情况下,蛋白a柱是有用的。蛋白g柱可用于纯化1-4亚类的人igg。重组融合蛋白a/g柱也可用于纯化所有这些类型的人抗体,因为融合蛋白提供蛋白a和蛋白g结合位点。因此,蛋白a/g融合蛋白可用于纯化人igg、iga、ige和igm。此外,蛋白l柱可用于纯化人igg、igm、iga、ige和igd,前提是靶抗体具有适当的κ(kappa)亚型轻链(即,vκi、vκiii和vκiv亚型);蛋白l柱也可用于纯化也具有适当κ链亚型的fab和scfv片段,因为蛋白l结合抗体的可变(v)链。
泵140位于第一保持盘管108的上游并且经由管道系统的导管192流体地联接至第一保持盘管108。该版本中的泵140采取注射泵的形式,所述注射泵流体地联接至第一缓冲液源196和第二缓冲液源200两者。在该版本中,第一缓冲液源196是洗脱缓冲液源,其可以提供洗脱缓冲溶液204,例如在蛋白a结合的抗体的情况下为酸性缓冲液;或在蛋白g结合的抗体的情况下,则为弱酸性(ph3或更低)缓冲液;本领域技术人员能够优化和选择用于结合的抗体的至泵140(最终至第一保持盘管108)的适当洗脱缓冲液,并且第二缓冲液源200是变性缓冲液(含有变性剂,所述变性剂破坏四级、三级或二级多肽结构)源,其可以将变性试剂208提供至泵140(并且最终提供至第一保持盘管108)。在其他版本中,泵140可以是不同类型的泵和/或不同的泵140可以用于缓冲液源196、200中的每个。
在一些版本中,变性试剂可以是或包括变性去污剂或离液剂。在其中变性试剂是或包括变性去污剂的那些版本中,变性去污剂优选选自由以下组成的组:十二烷基硫酸钠(sds)、胆酸钠、脱氧胆酸钠、甘氨胆酸钠、牛磺胆酸钠、牛磺脱氧胆酸钠、n-月桂酰肌氨酸、十二烷基硫酸锂、十六烷基三甲基溴化铵(ctab)和三甲基(十四烷基)溴化铵(ttab)。更优选地,变性去污剂是sds。在变性试剂是或包括离液剂的那些版本中,离液剂优选选自由以下组成的组:尿素、正丁醇、乙醇、氯化胍、高氯酸锂、乙酸锂、氯化镁、苯酚、2-丙醇、和硫脲。可替代地或另外地,变性试剂可以是或包括加热的流体,所述加热的流体当变性试剂被传送到反应室120时具有适于在反应室120中达到(如果不维持)预定温度(例如,约22℃至约120℃)的温度。
阀212位于泵140与第一和第二缓冲液源196、200之间,以选择性地一次将泵140流体地联接至仅缓冲液源196、200之一。更特别地,阀212可在第一位置(其中泵140与第一缓冲液源196流体地联接,并且泵140与第二缓冲液源200流体隔离)和第二位置(泵140与第二缓冲液源200流体地联接,并且泵140与第一缓冲液源196流体隔离)之间移动。换句话说,取决于阀212的位置,泵140选择性地流体地联接至第一缓冲液源196或第二缓冲液源200。
如上所述,这种版本的泵140是注射泵。注射泵140通常被配置为从缓冲液源196、200之一获得缓冲液,并将该缓冲液输出到第一保持盘管108。当阀212处于第一位置时,泵140可以从第一缓冲液源196获得(例如,吸入)洗脱缓冲溶液204,并且在需要时可以输出(例如,排出)洗脱缓冲溶液204至第一保持盘管108。相反,当阀212处于第二位置时,泵140可以从第二缓冲液源200获得(例如,吸入)变性试剂208,并且在需要时可以输出(例如,排出)变性试剂208至第一保持盘管108。
第二保持盘管116位于阀104、第一保持盘管108和第一柱112的下游。第二保持盘管116经由管道系统的导管216、220选择性地流体地联接至阀104的卫星通路166。第二保持盘管116还经由导管220和导管224选择性地流体地联接至第一柱112。三通阀228被布置在导管216、220、224之间,以促进选择性联接以便产生所需流体流,如下面更详细地描述的。
因此,当泵140以上述方式输出洗脱缓冲溶液204,阀104处于第二位置(其中中心通路160流体地联接到卫星通路165)时,第二保持盘管116被布置为经由阀104并通过第一柱112从第一保持盘管108接收洗脱缓冲溶液204。随着洗脱缓冲溶液204通过第一柱112,洗脱缓冲溶液204洗脱与第一柱112结合的基本上所有的多肽。三通阀228被操作以连接导管220、224,从而将第一柱112与第二保持盘管116流体地联接,使得包括洗脱缓冲溶液204和洗脱的多肽的洗脱液/多肽混合物经由导管220、224从第一柱112流到第二保持盘管116。
反应室120位于阀104和第一柱112的下游,并通过管道系统的导管232流体地联接至阀104的卫星通路167。在该版本中,通过使用泵140将变性试剂208输出到第一保持盘管108并将多通路阀104移动至第四位置(其中中心通路160流体地偶联到阀167的卫星通路167)从而促进变性试剂208从第一保持盘管108向反应室120的移动,来使反应室120从第二缓冲液源200部分地(如果不是完全地)预填充变性试剂208(即,在系统100运行之前填充)。然而,在其他版本中,反应室120可以在系统100的运行期间(例如,在第二保持盘管116接收洗脱缓冲溶液204之后)部分地或完全地填充变性试剂208,从另一个缓冲液源和/或以其他方式部分地或完全地填充变性试剂,或者根本不填充反应室120,在这种情况下,可以通过连接到反应室120的加热元件236向反应室120施加热。
在洗脱液/多肽混合物到达第二保持盘管116之后,将洗脱液/多肽混合物移动至反应室120。在该版本中,反应室120从第二保持盘管116间接接收洗脱液/多肽混合物。更特别地,三通阀228被操作以连接导管216、224,洗脱液/多肽混合物经由导管216、224从第二保持盘管116移动至多通路阀104的卫星通路166,阀104移动至第三位置(其中中心通路160流体地联接至卫星通路166),使混合物移动至第一保持盘管108,并且阀104移动至第四位置(其中中心通路160流体地联接至阀104的卫星通路167),使得混合物从第一保持盘管108移动至反应室120。在其他版本中,反应室120可以直接从第二保持盘管116接收洗脱液/多肽混合物,或者可以利用一种或多种不同组件和/或以不同顺序间接地从第二保持盘管116接收混合物。
在任何情况下,一旦洗脱液/多肽混合物到达反应室120,混合物中的多肽就会在反应室120中孵育,从而使反应室120中的多肽变性。例如,当反应室120至少部分地被变性试剂填充时,混合物中的多肽将在到达反应室120并与变性试剂反应后经历变性。在一些情况下,反应室120可同时或始终被连接至反应室120(例如,紧邻、围绕反应室120)的加热元件236加热,以帮助促进变性过程。换句话说,加热元件236可以向反应室120施加热,优选地具有约22℃至约120℃的热,并且更优选地具有约40℃的热以促进变性。加热元件236可以例如采取加热块,加热线圈,感应加热器,热泵,筒式加热器,电阻丝,加热的流体或适于加热反应室120的一个或多个部分的其他元件。无论如何,通过将热从加热元件236施加到反应室120,促进变性过程。然而,在其他情况下,反应室120不能填充变性试剂,并且可以仅通过从加热元件236施加热来促进变性过程。
在混合物中的多肽变性之后,反应室120被配置为接收裂解二硫键交联的还原试剂,从而还原变性的多肽。还原试剂可以选自由以下组成的组:二硫苏糖醇(dtt)、谷胱甘肽、β-巯基乙醇(β-me)和三(2-羧乙基)膦(tcep),并且通常由冷却容器240提供,所述容器可以例如采用温度为4℃的冷却器形式。在该版本中,冷却容器240位于阀104的下游并且具有第一室242,所述第一室242包含还原试剂并且经由管道系统的导管244流体地联接至阀104的卫星通路168。当阀104处于第五位置(其中中心通路160流体地联接至阀104的卫星通路168)时,第一室242将还原试剂供应至第一保持盘管108,并且然后当阀104处于(或返回)第四位置(其中中心通路160流体地联接至卫星通路167)时,还原试剂从第一保持盘管108移动至反应室120。因此,在该版本中,还原试剂经由第一保持盘管108间接地供应至反应室120。然而,在其他版本中,第一室242可以将还原试剂直接供应至反应室120(即,而无需将还原试剂移动至第一保持盘管108)。
在变性的多肽被还原之后,反应室120被配置为接收使反应室120中的巯基烷基化的烷基化剂,从而在反应室120中将变性和还原的多肽烷基化。烷基化剂优选是烷基化试剂,例如吲哚-3-乙酸(iaa),但是也可以使用其他烷基化剂。在该版本中,冷却容器240具有第二室248,所述第二室248包含烷基化剂并且经由管道系统的导管252流体地联接至阀104的卫星通路169。当阀104处于第六位置(其中中心通路160流体地联接至阀104的卫星通路169)时,第二室248将烷基化剂供应至第一保持盘管108,并且然后当阀104处于(或返回)第四位置时,烷基化剂从第一保持盘管108移动至反应室120。因此,在该版本中,烷基化剂经由第一保持盘管108间接地供应至反应室120。然而,在其他版本中,第二室248可直接将烷基化剂供应至反应室120(即,而无需将烷基化剂移动至第一保持盘管108)和/或烷基化剂可以从不同的冷却容器(例如,与冷却容器240分开的冷却容器)供应。
在此版本中,系统100还包括第一常开阀256,所述第一常开阀256流体地联接至反应室120并位于反应室120的下游。常开阀256具有与反应室120的出口264流体地连接的入口260,与第二废物室148流体地连接的第一出口268,和流体地连接至大气的第二出口272。当系统100运行时,更特别地讲,反应室120正在接收并填充洗脱液/多肽混合物、还原试剂、烷基化剂、以及在某些情况下的变性试剂,阀256时,常开阀256通常在打开位置或第一位置运行。在该打开位置,入口260与第一出口268流体地联接,并且入口260与第二出口272流体地隔离,使得当反应室120被填充超过其固定容积时,任何过量的内容物被引导至第二废物室148。然而,当例如反应室120不再接受上述内容物并且是时候清洗反应室120时,常开阀256可从打开位置移动(例如,通过向阀256施加电流)到关闭位置或第二位置。在该关闭位置,入口260与第二出口272流体地联接,并且入口260与第一出口268流体地隔离,使得反应室120的出口264暴露于大气。反过来,空气可以流入反应室120中,从而有利于从反应室120中去除内容物。
第二柱124,在本文中也称为脱盐柱124,优选采用尺寸排阻色谱柱的形式,其位于阀104的下游并且经由管道系统的导管276流体地联接至阀104的卫星通路170。因此,第二柱124被布置成从反应室120接收变性、还原并烷基化的多肽,洗脱缓冲溶液204,烷基化剂,还原试剂和变性试剂(当使用时)。在此版本中,第二柱124间接从反应室120接收这些材料。更特别地,当阀104处于(或移动至)第四位置(其中中心通路160流体地联接至卫星通路167)时,这些材料经由阀104从反应室120移动至第一保持盘管108,并且阀104移动至第七位置(其中中心通路160流体地联接至卫星通路170),使得材料从第一保持盘管108移动至第二柱124。在其他形式中,第二柱124可以直接从反应室120接收这些材料,或者可以利用一种或多种不同的组件和/或以不同的顺序间接地接收这些材料。
无论如何,当第二柱124接收变性、还原并烷基化的多肽,洗脱缓冲溶液204,烷基化剂,还原试剂和变性试剂(当使用时)时,第二柱124被配置为将变性、还原并烷基化的多肽与洗脱缓冲溶液204,烷基化剂,还原试剂和变性试剂(当使用时)(这些最终移动至第三废物室152)分离。因此,第二柱124在本文中可以被称为脱盐柱124。同时,第二柱124被配置为将多肽缓冲交换成所需的缓冲条件,所述条件允许第三柱128执行下述功能。
在此版本中,系统100还包括第二常开阀280,所述第二常开阀280流体地联接至第二柱124和第三柱128并且位于其之间。常开阀280具有与第二柱124的出口288流体地连接的入口284,与第三废物室152流体地连接的第一出口292,和流体地连接至第三柱128的第二出口296。当系统100在运行中时,常开阀280通常在打开位置或第一位置中运行。在该打开位置,入口284流体地联接至第一出口292,并且入口284与第二出口296流体地隔离,使得洗脱缓冲溶液204、烷基化剂、还原试剂和变性试剂被引导至第三废物室152。然而,当需要将脱盐的多肽从第二柱124移动至位于第二柱124下游的第三柱128时,常开阀280可从打开位置移动(例如,通过向阀280施加电流)到关闭位置或第二位置。在该关闭位置中,入口284流体地联接至第二出口296,并且入口284与第一出口通路292流体地隔离,使得第二柱124流体地联接至第三柱128,使得脱盐的多肽可以从第二柱124传送到第三柱128。在该版本中,第三柱128包括蛋白水解酶(例如,内肽酶,其选自由以下组成的组:胰蛋白酶、胰凝乳蛋白酶、弹性蛋白酶、嗜热菌蛋白酶、胃蛋白酶、谷氨酰内肽酶、脑啡肽酶、lys-c蛋白酶和金黄色葡萄球菌v8蛋白酶),使得第三柱128在本文中可以称为蛋白水解酶柱。无论如何,第三柱128消化从第二柱124获得的脱盐的多肽。
多肽在第三柱128中消化之后,可以将消化的多肽移动至分析装置156,其可以例如采用液相色谱装置、高效液相色谱装置、超高效液相色谱装置、质谱装置、聚糖分析装置,另一种分析装置或其组合的形式。在该版本中,分析装置156位于第三柱128的下游,并且经由管道系统的导管298流体地联接至第三柱128。因此,在该版本中,消化的多肽可以自动移动至分析装置156以进行分析(例如以进行定量和分离)。然而,在其他版本中,分析装置156不是系统100的一部分(例如,未流体地联接至第三柱128),在这种情况下,消化的多肽可以以不同的方式(例如手动)移动至分析装置156。
如上所述,系统100还包括控制器132,在此版本中,控制器132通信地联接或连接至系统100的各个组件,以通过向系统100的各个组件传输信号(例如控制信号,数据)以及从系统100的各个组件接收信号(例如数据)来监测并促进或指导系统100的上述运行。控制器132可以紧邻系统100的其他组件放置(例如,在与系统100相同的环境中),或者可以远离系统100的其他组件放置。如图所示,控制器132经由通信网络300通信地联接或连接至多通路阀104,经由通信网络328通信地联接或连接至泵140,经由通信网络332通信地联接或连接至分析装置156,经由通信网络340通信地联接或连接至加热元件236,经由通信网络344通信地联接或连接至第一常开阀256,以及经由通信网络348通信地联接或连接至第二常开阀280。在其他版本中,控制器132可以通信地联接或连接至系统100的更多或更少的组件,例如,第一保持盘管108、第一柱112、第二保持盘管116、反应室120、第二柱124、第三柱128、容器136、三通阀228和/或冷却容器240。
如本文所使用的,短语“通信地联接”和“连接”被定义为意指直接联接或连接或通过一个或多个中间组件间接联接或连接。这样的中间组件可以包括基于硬件和/或软件的组件。应当理解,网络300-348可以是无线网络、有线网络或有线和无线网络(例如,蜂窝电话网络和/或802.11x兼容网络)的组合,并且可以包括公共可访问的网络,例如因特网、专用网络或其组合。网络300-348的类型和配置取决于实现方式,并且可以使用任何类型的通信网络,所述通信网络促进现在或以后开发的控制器132与系统100的组件之间的所描述的通信。
如图2所示,控制器132包括处理器352、存储器356、通信接口360和计算逻辑364。处理器352可以是通用处理器、数字信号处理器、专用集成电路(asic)、现场可编程门阵列、图形处理单元、模拟电路、数字电路或任何其他已知或以后开发的处理器。处理器352根据存储器356中的指令进行操作。存储器356可以是易失性存储器或非易失性存储器。存储器356可以包括只读存储器(rom)、随机存取存储器(ram)、闪存、电子可擦除程序只读存储器(eeprom)或其他类型的存储器中的一个或多个。存储器356可以包括光、磁(硬盘)或任何其他形式的数据存储装置。
提供通信接口360以经由网络300-348实现或促进控制器132与制冷系统100的组件之间的电子通信。通信接口360可以是或包括例如一个或多个通用串行总线(usb)端口、一个或多个以太网端口和/或一个或多个其他端口或接口。电子通信可以经由任何已知的通信协议发生,例如,包括usb、rs-232、rs-485、wifi、蓝牙和/或任何其他合适的通信协议。
逻辑364通常包括体现为存储在存储器356上的计算机可读指令的一个或多个控制例程和/或一个或多个子例程。控制例程和/或子例程可以执行pid(比例-积分-微分)、模糊逻辑、非线性或任何其他合适类型的控制。处理器352通常执行逻辑364以执行与系统100的运行有关的动作。
一般而言,逻辑364在执行时使处理器352控制系统100的组件,尤其是多通路阀104,泵140,加热元件236,第一和第二常开阀256、280,和分析装置156,使得系统100以本文讨论的所需方式操作。更特别地,逻辑364在执行时可使处理器352(i)将多通路阀104移动至本文所述的任何位置或之间,从而流体地联接如上所述的系统100的各个组件,(ii)控制泵140(例如,使泵140获得并输出洗脱缓冲溶液204或变性试剂208),(iii)控制加热元件236(当在系统100中使用时)以选择性地将热施加至反应室120(及其内容物),(iv)控制第一常开阀256,(v)控制第二常开阀280,(vi)控制分析装置156,并执行其他所需功能。
例如,当期望对包含多肽的产物的样品进行实时测定时,逻辑364可由处理器352执行以将阀104定位在上述第一位置,通过导管180、通路164、通路160将产物的样品从容器136移动至第一保持盘管108,将阀104定位在上述第二位置,并通过导管184、通路160、164和导管188将样品从第一保持盘管108移动至并通过多肽结合柱112。反过来,样品中的基本上所有多肽都与柱112结合,使得样品中的多肽与样品的其余部分分开,所述其余部分经由导管220、224和第二保持盘管116传送第一废物室144。
逻辑364可由处理器352进一步执行,以使泵140从第一缓冲液源196获得洗脱缓冲溶液204,并经由导管192将洗脱缓冲溶液204输出至第一保持盘管108。在某些情况下,可能需要将泵140从第二位置移动至第一位置(以将泵140与第一缓冲液源196流体地联接),但是在其他情况下,泵140可能已经处于第一位置。在任何情况下,逻辑364均可由处理器352执行,以经由导管184、通路160、通路165和导管188、220和224,将洗脱缓冲溶液204从第一保持盘管108移动至并通过第一柱112并移动至第二保持盘管116。以这种方式,洗脱缓冲溶液204洗脱与第一柱112结合的基本上所有的多肽,并且包含洗脱缓冲溶液204和洗脱的多肽的洗脱液/多肽混合物从第一柱112流动至第二保持盘管116。
逻辑364可由处理器352进一步执行以将阀104移动至上述第三位置,经由导管224、导管216、通路166、通路160和导管184将洗脱液/多肽混合物从第二保持盘管116移动至第一保持盘管108,将阀104移动至上述第四位置,并经由导管184、通路160、通路167和导管232将洗脱液/多肽混合物从第一保持盘管108移动至反应室120。反过来,将洗脱液/多肽混合物中的多肽与变性试剂208和/或在加热元件236施加的热的存在下在反应室120中孵育,从而使多肽变性。
逻辑364可由处理器352进一步执行以将阀104移动至上述第五位置,经由导管244、通路168、通路160和导管184将还原试剂从冷却容器240的第一室242移动至第一保持盘管108,将阀104移动返回至第四位置,并经由导管184、通路160、通路167和导管232将还原试剂从第一保持盘管108移动至反应室120。在到达反应室120后,还原试剂裂解二硫键交联,从而这还原反应室120中的变性的多肽。
逻辑364可由处理器352进一步执行以将阀104移动至上述第六位置,经由导管252、通路169、通路160和导管184将烷基化剂从冷却容器240的第二室248移动至第一保持盘管108,将阀104移动返回至第四位置,并经由导管184、通路160、通路167和导管232将烷基化剂从第一保持盘管108移动至反应室120。在到达反应室120后,烷基化剂使反应室120中的巯基烷基化,从而这使反应室120中的变性和还原的多肽烷基化。
逻辑364可由处理器352进一步执行以将阀104移动至上述第四位置(如果尚未在所述位置),经由导管232、通路167、通路160和导管184,将变性、还原并烷基化的多肽,洗脱缓冲溶液204,烷基化剂,还原试剂和变性试剂(当使用时)从反应室120移动至第一保持盘管108,将阀104移动至上述第七位置,并且经由导管184、通路160、通路170和导管276,将变性、还原并烷基化的多肽,洗脱缓冲溶液204,烷基化剂,还原试剂和变性试剂(当使用时)从第一保持盘管108移动至脱盐柱124。反过来,脱盐柱124将变性、还原并烷基化的多肽与洗脱缓冲溶液204,烷基化剂,还原试剂和变性试剂分离,所述洗脱缓冲溶液204,烷基化剂,还原试剂和变性试剂传送至或移动至第三废物室152。
在变性、还原并烷基化的多肽之后的某个点,将洗脱缓冲溶液204、烷基化剂、还原试剂和变性试剂(当使用时)从反应室120移动至第一保持盘管108,逻辑364可由处理器352进一步执行以将常开阀256从其打开的第一位置(其中室120的出口264流体地联接至第二废物室148,以将不能装入反应室120(由于其被填充超过其固定容积)中的内容物引导至第二废物室148)移动至其关闭的第二位置(其中出口264流体地联接至大气,使得空气可以流入反应室120中,从而有利于从反应室120中去除内容物)。常开阀256可以在反应室120被排空之后立即返回到打开的第一位置,或者可以在稍后的时间点返回到打开的第一位置。
在脱盐柱124将变性、还原并烷基化的多肽与其他材料分离之后,逻辑364可由处理器352进一步执行以将常开阀280从其打开的第一位置(其中阀280的入口流体地联接至第三废物室152)移动至其关闭的第二位置(其中阀280的入口流体地联接至蛋白水解酶柱128)。反过来,逻辑364可以由处理器352执行,以将脱盐的(或分离的)多肽从脱盐柱124移动至蛋白水解酶柱128(其消化脱盐的多肽)。
在多肽被消化之后,至少在此版本中,逻辑364可以由处理器352进一步执行,以将消化的多肽从蛋白水解酶柱128移动至分析装置156以分析多肽,并使分析装置156执行所需的分析。例如,逻辑364可以在由处理器352执行时使分析装置156分离并定量多肽。
在其他版本中,逻辑364在由处理器352执行时可以使得执行附加的、较少的和/或不同的功能。作为实例,逻辑364在由处理器352执行时可以不将消化的多肽从柱128移动至分析装置156,或者不使分析装置156执行所需的分析。此外,在其他版本中,逻辑364可以由处理器352以与本文所述不同的顺序执行。最后,应当理解,逻辑364可以由处理器352执行任意不同次数,因为系统100可以用于对多个样品(来自同一产物和/或来自不同产物)进行实时分析。
图3a-图3c示出了联机和实时mam测定研究的结果,所述研究被设计为监测系统100在制备包含双特异性t细胞衔接
治疗性多肽
蛋白质,包括与以下一种或多种结合的蛋白质,可用于所披露的装置和方法。这些包括cd蛋白,包括cd3、cd4、cd8、cd19、cd20、cd22、cd30和cd34;包括干扰受体结合的那些。her受体家族蛋白,包括her2、her3、her4和egf受体。细胞粘附分子,例如,lfa-i、moi、pl50、pl95、vla-4、icam-i、vcam和αv/β3整联蛋白。生长因子,例如血管内皮生长因子(“vegf”)、生长激素、甲状腺刺激素、卵泡刺激素、黄体生成激素、生长激素释放因子、甲状旁腺激素、米勒管抑制物质(mullerian-inhibitingsubstance)、人类巨噬细胞炎性蛋白(mip-i-α)、促红细胞生成素(epo)、神经生长因子(诸如ngf-β)、血小板源性生长因子(pdgf)、成纤维细胞生长因子(包括例如afgf和bfgf)、表皮生长因子(egf)、转化生长因子(tgf)(其中包括tgf-α和tgf-β,包括tgf-βl、tgf-β2、tgf-β3、tgf-β4或tgf-β5)、胰岛素样生长因子-i和胰岛素样生长因子-ii(igf-i和igf-ii)、des(l-3)-igf-i(脑igf-i)和骨诱导因子。胰岛素和胰岛素相关蛋白,包括胰岛素、胰岛素a链、胰岛素b链、胰岛素原和类胰岛素生长因子结合蛋白。凝血蛋白和凝血相关蛋白,尤其诸如,viii因子、组织因子、范威尔邦德(vonwillebrand)因子、蛋白c、α-1-抗胰蛋白酶、纤溶酶原激活剂(诸如尿激酶和组织纤溶酶原激活剂(“t-pa”))、邦巴辛(bombazine)、凝血酶、和血小板生成素;(vii)其他血液和血清蛋白,包括但不限于白蛋白、ige和血型抗原。菌落刺激因子及其受体,其中包括以下:m-csf,gm-csf和g-csf,及其受体,例如csf-1受体(c-fms)。受体和受体相关蛋白,包括例如flk2/flt3受体、肥胖(ob)受体、ldl受体、生长激素受体、血小板生成素受体(“tpo-r”,“c-mpl”)、胰高血糖素受体、白介素受体、干扰素受体、t细胞受体、干细胞因子受体(例如c-kit)和其他受体。受体配体,包括例如ox40l、ox40受体的配体。神经营养因子,包括骨源性神经营养因子(bdnf)和神经营养蛋白-3、神经营养蛋白-4、神经营养蛋白-5或神经营养蛋白-6(nt-3、nt-4、nt-5或nt-6)。松弛素a链、松弛素b链和松弛素原;干扰素和干扰素受体,包括例如干扰素-α、干扰素-β和干扰素-γ,及其受体。白介素和白介素受体,包括il-i至il-33和il-i至il-33受体,例如il-8受体,等等。病毒抗原,包括aids包膜病毒抗原。脂蛋白、降钙素、胰高血糖素、心钠素、肺表面活性剂、肿瘤坏死因子-α和-β、脑啡肽酶、rantes(受激活调节的正常t细胞表达与分泌的)、小鼠促性腺激素相关肽、dna酶、抑制素和激活素。整联蛋白、蛋白a或d、类风湿因子、免疫毒素、骨形态发生蛋白(bmp)、超氧化物歧化酶、表面膜蛋白、衰变促进因子(daf)、aids包膜、转运蛋白、归巢受体、地址素、调节蛋白、免疫粘附素、抗体。肌生长抑制素、tall蛋白(包括tall-i)、淀粉样蛋白(包括但不限于淀粉样β蛋白)、胸腺基质淋巴细胞生成素(“tslp”)、rank配体(“opgl”)、c-kit、tnf受体(包括tnf受体1型)、trail-r2、血管生成素和任何上述物质的生物活性片段或类似物或变体。
示例性的多肽和抗体包括
适用于所述方法和药物配制品的抗体实例包括表1中所示的抗体。适合的抗体的其他实例包括英夫利昔单抗(infliximab)、贝伐单抗(bevacizumab)、西妥昔单抗(cetuximab)、兰尼单抗(ranibizumab)、帕利珠单抗(palivizumab)、阿巴伏单抗(abagovomab)、阿昔单抗(abciximab)、阿克托克单抗(actoxumab)、阿达木单抗(adalimumab)、阿非莫单抗(afelimomab)、阿托珠单抗(afutuzumab)、阿珠单抗(alacizumab)、培化阿珠单抗(alacizumabpegol)、ald518、阿仑单抗(alemtuzumab)、阿利库单抗(alirocumab)、阿妥莫单抗(altumomab)、阿麦妥昔单抗(amatuximab)、马安那莫单抗(anatumomabmafenatox)、安芦珠单抗(anrukinzumab)、阿泊珠单抗(apolizumab)、阿西莫单抗(arcitumomab)、阿塞珠单抗(aselizumab)、阿替奴单抗(altinumab)、阿替珠单抗(atlizumab)、阿托立木单抗(atorolimiumab)、托珠单抗(tocilizumab)、巴匹珠单抗(bapineuzumab)、巴利昔单抗(basiliximab)、巴维昔单抗(bavituximab)、贝妥莫单抗(bectumomab)、贝利木单抗(belimumab)、苯拉利珠单抗(benralizumab)、柏替木单抗(bertilimumab)、贝索单抗(besilesomab)、贝伐珠单抗(bevacizumab)、贝洛托单抗(bezlotoxumab)、比西单抗(biciromab)、比伐珠单抗(bivatuzumab)、莫-比伐珠单抗(bivatuzumabmertansine)、博纳吐单抗(blinatumomab)、布索珠单抗(blosozumab)、本妥昔单抗(brentuximabvedotin)、巴列津单抗(briakinumab)、布洛鲁单抗(brodalumab)、康纳单抗(canakinumab)、莫坎妥珠单抗(cantuzumabmertansine)、莫坎妥珠单抗(cantuzumabmertansine)、卡普赛珠单抗(caplacizumab)、卡罗单抗喷地肽(capromabpendetide)、卡鲁单抗(carlumab)、卡妥索单抗(catumaxomab)、cc49、西利珠单抗(cedelizumab)、赛妥珠单抗(certolizumabpegol)、西妥昔单抗(cetuximab)、泊西他珠单抗(citatuzumabbogatox)、西妥木单抗(cixutumumab)、克拉扎珠单抗(clazakizumab)、克立昔单抗(clenoliximab)、克伐珠单抗(clivatuzumabtetraxetan)、可那木单抗(conatumumab)、克雷内治单抗(crenezumab)、cr6261、达西珠单抗(dacetuzumab)、达克珠单抗(daclizumab)、达罗土珠单抗(dalotuzumab)、达雷木单抗(daratumumab)、地莫米佐单抗(demcizumab)、地诺单抗(denosumab)、地莫单抗(detumomab)、阿托度单抗(dorlimomabaritox)、德罗图单抗(drozitumab)、杜力戈图单抗(duligotumab)、杜匹鲁单抗(dupilumab)、依美昔单抗(ecromeximab)、依库丽单抗(eculizumab)、埃巴单抗(edobacomab)、依决洛单抗(edrecolomab)、依法利珠单抗(efalizumab)、依芬古单抗(efungumab)、埃罗妥珠单抗(elotuzumab)、艾西莫单抗(elsilimomab)、埃文单抗(enavatuzumab)、培化恩莫单抗(enlimomabpegol)、恩诺珠单抗(enokizumab)、依诺替库单抗(enoticumab)、埃斯托西单抗(ensituximab)、西依匹莫单抗(epitumomabcituxetan)、依帕珠单抗(epratuzumab)、厄瑞奴单抗(erenumab)、厄利珠单抗(erlizumab)、厄马索单抗(ertumaxomab)、埃达珠单抗(etaracizumab)、依卓利珠单抗(etrolizumab)、依伏库单抗(evolocumab)、艾韦单抗(exbivirumab)、法索单抗(fanolesomab)、法拉莫单抗(faralimomab)、法拉图珠单抗(farletuzumab)、法希奴单抗(fasinumab)、fbta05、非维珠单抗(felvizumab)、非扎奴单抗(fezakinumab)、费希腊妥单抗(ficlatuzumab)、芬妥木单抗(figitumumab)、弗兰托单抗(flanvotumab)、芳妥珠单抗(fontolizumab)、弗罗鲁单抗(foralumab)、福拉韦单抗(foravirumab)、夫苏木单抗(fresolimumab)、弗兰单抗(fulranumab)、弗图希单抗(futuximab)、加利昔单抗(galiximab)、盖尼柱单抗(ganitumab)、盖坦德单抗(gantenerumab)、加维莫单抗(gavilimomab)、吉妥珠单抗奥佐米星(gemtuzumabozogamicin)、吉伏珠单抗(gevokizumab)、吉仁土昔单抗(girentuximab)、维德汀单抗(glembatumumabvedotin)、戈利木单抗(golimumab)、戈利昔单抗(gomiliximab)、gs6624、替伊立珠单抗(ibalizumab)、替伊莫单抗(ibritumomabtiuxetan)、依库单抗(icrucumab)、伊戈伏单抗(igovomab)、英西单抗(imciromab)、英戈土珠单抗(imgatuzumab)、英克拉库单抗(inclacumab)、依坦希单抗(indatuximabravtansine)、英夫利西单抗(infliximab)、英妥木单抗(intetumumab)、伊诺莫单抗(inolimomab)、伊珠单抗奥佐米星(inotuzumabozogamicin)、伊匹木单抗(ipilimumab)、艾雷妥木单抗(iratumumab)、依拓珠单抗(itolizumab)、希凯珠单抗(ixekizumab)、凯利昔单抗(keliximab)、拉贝珠单抗(labetuzumab)、来金珠单抗(lebrikizumab)、来马索单抗(lemalesomab)、乐地单抗(lerdelimumab)、来沙木单抗(lexatumumab)、利韦单抗(libivirumab)、利格珠单抗(ligelizumab)、林妥珠单抗(lintuzumab)、立鲁单抗(lirilumab)、莫-洛伏珠单抗(lorvotuzumabmertansine)、鲁卡木单抗(lucatumumab)、鲁昔单抗(lumiliximab)、马帕木单抗(mapatumumab)、马司莫单抗(maslimomab)、美力姆单抗(mavrilimumab)、马妥珠单抗(matuzumab)、美泊利单抗(mepolizumab)、美替木单抗(metelimumab)、米拉珠单抗(milatuzumab)、明瑞莫单抗(minretumomab)、米妥莫单抗(mitumomab)、莫格穆里单抗(mogamulizumab)、莫罗木单抗(morolimumab)、莫他珠单抗(motavizumab)、莫希土姆单抗(moxetumomabpasudotox)、莫罗单抗-cd3(muromonab-cd3)、他那可单抗(nacolomabtafenatox)、纳米鲁单抗(namilumab)、他那莫单抗(naptumomabestafenatox)、纳瑞特单抗(narnatumab)、那他珠单抗(natalizumab)、奈巴库单抗(nebacumab)、奈昔木单抗(necitumumab)、奈瑞莫单抗(nerelimomab)、耐西维单抗(nesvacumab)、尼妥珠单抗(nimotuzumab)、纳武单抗(nivolumab)、巯诺莫单抗(nofetumomabmerpentan)、奥卡土珠单抗(ocaratuzumab)、奥瑞珠单抗(ocrelizumab)、奥度莫单抗(odulimomab)、奥法木单抗(ofatumumab)、奥拉图单抗(olaratumab)、奥鲁凯珠单抗(olokizumab)、奥马珠单抗(omalizumab)、欧那土珠单抗(onartuzumab)、莫奥珠单抗(oportuzumabmonatox)、奥戈伏单抗(oregovomab)、奥泰单抗(orticumab)、奥昔珠单抗(otelixizumab)、欧西鲁单抗(oxelumab)、欧赞尼珠单抗(ozanezumab)、欧拉丽珠单抗(ozoralizumab)、帕吉昔单抗(pagibaximab)、帕利珠单抗(palivizumab)、帕尼单抗(panitumumab)、帕诺库单抗(panobacumab)、帕萨土珠单抗(parsatuzumab)、帕考珠单抗(pascolizumab)、帕特立珠单抗(pateclizumab)、帕图单抗(patritumab)、帕尼单抗(pemtumomab)、培拉凯珠单抗(perakizumab)、培妥珠单抗(pertuzumab)、培克珠单抗(pexelizumab)、皮地利珠单抗(pidilizumab)、平妥莫单抗(pintumomab)、普拉库鲁单抗(placulumab)、拍珠单抗(ponezumab)、普立昔单抗(priliximab)、普托木单抗(pritumumab)、pro140、坤立珠单抗(quilizumab)、雷库图单抗(racotumomab)、雷德图单抗(radretumab)、雷韦单抗(rafivirumab)、雷莫芦单抗(ramucirumab)、雷珠单抗(ranibizumab)、雷昔库单抗(raxibacumab)、瑞加韦单抗(regavirumab)、瑞利珠单抗(reslizumab)、利妥木单抗(rilotumumab)、利妥昔单抗(rituximab)、罗妥木单抗(robatumumab)、罗勒杜单抗(roledumab)、罗姆苏珠单抗(romosozumab)、隆他利珠单抗(rontalizumab)、罗利珠单抗(rovelizumab)、鲁利珠单抗(ruplizumab)、沙玛立珠单抗(samalizumab)、沙鲁单抗(sarilumab)、沙妥莫单抗喷地肽(satumomabpendetide)、苏金单抗(secukinumab)、司韦单抗(sevirumab)、西罗珠单抗(sibrotuzumab)、西法木单抗(sifalimumab)、司妥昔单抗(siltuximab)、西姆土珠单抗(simtuzumab)、西利珠单抗(siplizumab)、希瑞库单抗(sirukumab)、苏兰珠单抗(solanezumab)、苏力图单抗(solitomab)、松普希珠单抗(sonepcizumab)、松妥珠单抗(sontuzumab)、司他芦单抗(stamulumab)、硫索单抗(sulesomab)、索维单抗(suvizumab)、他贝鲁单抗(tabalumab)、他珠单抗(tacatuzumabtetraxetan)、他度珠单抗(tadocizumab)、他利珠单抗(talizumab)、他尼珠单抗(tanezumab)、帕他莫单抗(taplitumomabpaptox)、替非珠单抗(tefibazumab)、阿替莫单抗(telimomabaritox)、替妥莫单抗(tenatumomab)、替非珠单抗(tefibazumab)、替奈昔单抗(teneliximab)、替利珠单抗(teplizumab)、替普单抗(teprotumumab)、替扎贝鲁单抗(tezepelumab)、tgn1412、曲美木单抗(tremelimumab)、替西木单抗(ticilimumab)、替拉珠单抗(tildrakizumab)、替加珠单抗(tigatuzumab)、tnx-650、托珠单抗(tocilizumab)、托利珠单抗(toralizumab)、托西莫单抗(tositumomab)、曲洛青木单抗(tralokinumab)、曲妥珠单抗(trastuzumab)、trbs07、曲加立珠单抗(tregalizumab)、西莫白介素单抗(tucotuzumabcelmoleukin)、妥韦单抗(tuvirumab)、乌波利土西单抗(ublituximab)、乌瑞鲁单抗(urelumab)、乌珠单抗(urtoxazumab)、优特克单抗(ustekinumab)、伐利昔单抗(vapaliximab)、维特立珠单抗(vatelizumab)、维多珠单抗(vedolizumab)、维妥珠单抗(veltuzumab)、维帕莫单抗(vepalimomab)、维西库单抗(vesencumab)、维西珠单抗(visilizumab)、伏洛昔单抗(volociximab)、伏妥土珠单抗(vorsetuzumabmafodotin)、伏妥莫单抗(votumumab)、扎芦木单抗(zalutumumab)、扎木单抗(zanolimumab)、扎土希单抗(zatuximab)、齐拉木单抗(ziralimumab)、阿佐莫单抗(zolimomabaritox)。
抗体还包括阿达木单抗、贝伐单抗、博纳吐单抗、西妥昔单抗、可那木单抗、地诺单抗、依库丽单抗、厄瑞奴单抗、依伏库单抗、英夫利昔单抗、那他珠单抗、帕尼单抗、利妥木单抗、利妥昔单抗、罗姆苏珠单抗、替扎贝鲁单抗、和曲妥珠单抗、和从表1选择的抗体。
表1
治疗性抗体的实例
*适用于患者施用的示例性浓度;^hc-抗体重链;lc-抗体轻链。
基于前面的描述,应当理解,本文所述的装置、系统和方法有助于基本上实时地执行样品的测定。因此,与常规方法相比可以更快地进行所述测定并获得所需结果。
还应当理解,本文所述的装置、系统和方法允许使用系统100的联机实时测定的制备过程易于监测,这又可以减轻风险并延长产物的生产运行。特别地,可以通过例如使用诸如控制器132之类的控制器和/或由系统100的操作者手动确定系统100中的条件是否最佳,即,它们是否满足预定的性能阈值来监测该过程。如图3b和图3c所示,例如可以获取四个参考肽rp1、rp2、rp3和rp4的ms峰高(以离子计数表示),并在方法鉴定期间针对那些参考肽的历史值进行比较,以确定系统100中的条件是否是最佳的(以及它们是最佳的),使得可以开始、继续或延长所述生产运行。然而,当确定系统100中的条件不是最佳时,可以调节至少一种细胞培养构成,直到封闭系统中的条件最佳为止。可以调整的细胞培养构成的实例包括但不限于:ph、压力、温度、培养基流量(例如,培养基流速、培养基进料速率)、培养基含量(包括氨基酸、营养物质、糖、缓冲液)、气体处理策略(氧气和二氧化碳的混合、气体速率)、搅拌(例如,搅拌速率)、添加剂(例如金属添加剂、糖添加剂)、添加剂(例如,消泡剂)进料速率和灌注速率。在一些情况下,可能只需要调整一种细胞培养构成,以使封闭系统中的条件达到最佳,而在其他情况下,可能需要调整多种细胞培养构成。可替代地,当确定条件不是最佳的时,或者即使在调整了至少一种细胞培养构成之后系统100中的条件也不是最佳的时,系统100的控制器和/或操作者可以关闭系统100。
以此方式,当条件不是最佳的或者在其他方面不希望继续系统100的运行时,本文所述的装置、系统和方法还减轻了系统100的继续运行所涉及的风险。特别地,可以通过以下来减轻风险:确定(例如,计算或获得)与系统100的当前运行有关的过程参数和产物质量数据,例如ph、温度、氧溶解、细胞生存力、细胞密度、滴度、聚集、电荷变化、糖基化等,确定所述过程参数和产物质量数据是否满足预定的风险阈值(通过控制器例如控制器132和/或对系统100的操作者输入的应答,在系统100的运行之前确定),并且然后根据所述过程参数和产物质量数据是否满足所述预定的风险阈值来确定是否继续、停止或调整系统100的运行。预定的风险阈值可以例如通过以下来确定:(1)应用可用的过程参数数据和产物质量数据来计算与系统100或一些其他类似系统的先前运行相关的平均历史多变量(mv)数据,并且然后,(2)将计算出的平均历史mv数据建立为阈值(所述阈值可以是计算出的平均历史mv数据本身,或是基于计算出的平均历史mv数据的某些值或一组值。在一个实例中,预定的风险阈值可以表示与计算出的平均历史mv数据的可接受的偏差(例如,三个标准偏差)。可替代地或另外地,可以根据来自系统100的操作者的输入来确定预定的风险阈值。在一些情况下,当与系统100的当前运行相关的过程参数和产物质量数据不满足(例如,超过)预定的风险阈值时,系统100可以关闭。然而,在其他情况下,当与系统100的当前运行相关的过程参数和产物质量数据不满足(例如,超过)预定的风险阈值时,或者当过程参数和产物质量数据满足但接近预定的风险阈值时,可以调整系统100。
此外,申请人已经发现,本文描述的装置、系统和方法还允许使用系统100的生产运行得以延长。常规方法通常最多允许32至40天的生产运行。然而,申请人已经发现,本文所述的装置、系统和方法允许50-80(如果不是100)的群体倍增数,即,大约50-80(如果不是100)天生产运行。因此,在监测系统100的运行以确保产物满足质量目标并且减轻风险的同时,可以获得更多的产物。
本文描述了本披露的优选实施例,包括已知诸位发明人用于进行本披露的一种或多种最佳模式。尽管在此示出并描述了许多实例,但是本领域技术人员将容易理解,各个实施例的细节不必相互排斥。相反,本领域技术人员在阅读本文的教导后应该能够将一个实施例的一个或多个特征与其余实施例的一个或多个特征相组合。此外,还应当理解,所示出的实施例仅是示例性的,并且不应被视为限制本披露的范围。除非本文另外指示或另外明显地与上下文矛盾,否则本文所述的所有方法能以任何合适顺序进行。本文提供的任何和所有实例或示例性语言(诸如“例如”)的使用仅旨在更好地阐明本披露的一个或多个示例性实施例的各个方面,并且不对本披露的范围构成限制。说明书中的语言不应当被解释为指示任何未要求保护的要素为实践本披露所必需的。
序列表
<110>安进公司
c-h·吴
<120>进行实时样品测定的系统和方法
<130>32263/51800
<150>62/539,803
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<211>465
<212>prt
<213>智人
<400>10
metgluleuglyleucystrpvalpheleuvalalaileleuglugly
151015
valglncysgluvalglnleuvalgluserglyglyglyleuvalgln
202530
proglyglyserleuargleusercysalaalaserglyphethrphe
354045
sersertyrsermetasntrpvalargglnalaproglylysglyleu
505560
glutrpvalsertyrileserserserglyserseriletyrtyrala
65707580
aspservallysglyargphethrileserargaspasnalalysasn
859095
serleutyrleuglnmetasnserleuargaspgluaspthralaval
100105110
tyrtyrcysalaarggluargtyrtyrglyaspthrpropheasptyr
115120125
trpglyglnglythrleuvalthrvalserseralaserthrlysgly
130135140
proservalpheproleualaprocysserargserthrsergluser
145150155160
thralaalaleuglycysleuvallysasptyrpheprogluproval
165170175
thrvalsertrpasnserglyalaleuthrserglyvalhisthrphe
180185190
proalavalleuglnserserglyleutyrserleuserservalval
195200205
thrvalproserserasnpheglythrglnthrtyrthrcysasnval
210215220
asphislysproserasnthrlysvalasplysthrvalgluarglys
225230235240
cyscysvalglucysproprocysproalaproprovalalaglypro
245250255
servalpheleupheproprolysprolysaspthrleumetileser
260265270
argthrprogluvalthrcysvalvalvalaspvalserhisgluasp
275280285
progluvalglnpheasntrptyrvalaspglyvalgluvalhisasn
290295300
alalysthrlysproargglugluglnpheasnserthrpheargval
305310315320
valservalleuthrvalvalhisglnasptrpleuasnglylysglu
325330335
tyrlyscyslysvalserasnlysglyleuproalaproileglulys
340345350
thrileserlysthrlysglyglnproarggluproglnvaltyrthr
355360365
leuproproserarggluglumetthrlysasnglnvalserleuthr
370375380
cysleuvallysglyphetyrproseraspilealavalglutrpglu
385390395400
serasnglyglnprogluasnasntyrlysthrthrproprometleu
405410415
aspseraspglyserphepheleutyrserlysleuthrvalasplys
420425430
serargtrpglnglnglyasnvalphesercysservalmethisglu
435440445
alaleuhisasnhistyrthrglnlysserleuserleuserprogly
450455460
lys
465
<210>11
<211>233
<212>prt
<213>智人
<400>11
metserproserglnleuileglypheleuleuleutrpvalproala
151015
serargglygluilevalleuthrglnserproasppheglnserval
202530
thrprolysglulysvalthrilethrcysargalaserglnserile
354045
glyserserleuhistrptyrglnglnlysproaspglnserprolys
505560
leuleuilelystyralaserglnserpheserglyvalproserarg
65707580
pheserglyserglyserglythraspphethrleuthrileasnser
859095
leuglualagluaspalaalaalatyrtyrcyshisglnserserser
100105110
leuproleuthrpheglyglyglythrlysvalgluilelysargthr
115120125
valalaalaproservalpheilepheproproseraspgluglnleu
130135140
lysserglythralaservalvalcysleuleuasnasnphetyrpro
145150155160
argglualalysvalglntrplysvalaspasnalaleuglnsergly
165170175
asnserglngluservalthrgluglnaspserlysaspserthrtyr
180185190
serleuserserthrleuthrleuserlysalaasptyrglulyshis
195200205
lysvaltyralacysgluvalthrhisglnglyleuserserproval
210215220
thrlysserpheasnargglyglucys
225230
<210>12
<211>463
<212>prt
<213>智人
<400>12
metglyserthralaileleualaleuleuleualavalleuglngly
151015
valcysalagluvalglnleumetglnserglyalagluvallyslys
202530
proglygluserleulysilesercyslysglyserglytyrserphe
354045
serphehistrpilealatrpvalargglnmetproglylysglyleu
505560
glutrpmetglyileilehisproglyalaseraspthrargtyrser
65707580
proserpheglnglyglnvalthrileseralaaspasnserasnser
859095
alathrtyrleuglntrpserserleulysalaseraspthralamet
100105110
tyrphecysalaargglnarggluleuasptyrpheasptyrtrpgly
115120125
glnglythrleuvalthrvalserseralaserthrlysglyproser
130135140
valpheproleualaprocysserargserthrsergluserthrala
145150155160
alaleuglycysleuvallysasptyrpheprogluprovalthrval
165170175
sertrpasnserglyalaleuthrserglyvalhisthrpheproala
180185190
valleuglnserserglyleutyrserleuserservalvalthrval
195200205
proserserasnpheglythrglnthrtyrthrcysasnvalasphis
210215220
lysproserasnthrlysvalasplysthrvalgluarglyscyscys
225230235240
valglucysproprocysproalaproprovalalaglyproserval
245250255
pheleupheproprolysprolysaspthrleumetileserargthr
260265270
progluvalthrcysvalvalvalaspvalserhisgluaspproglu
275280285
valglnpheasntrptyrvalaspglyvalgluvalhisasnalalys
290295300
thrlysproargglugluglnpheasnserthrpheargvalvalser
305310315320
valleuthrvalvalhisglnasptrpleuasnglylysglutyrlys
325330335
cyslysvalserasnlysglyleuproalaproileglulysthrile
340345350
serlysthrlysglyglnproarggluproglnvaltyrthrleupro
355360365
proserarggluglumetthrlysasnglnvalserleuthrcysleu
370375380
vallysglyphetyrproseraspilealavalglutrpgluserasn
385390395400
glyglnprogluasnasntyrlysthrthrproprometleuaspser
405410415
aspglyserphepheleutyrserlysleuthrvalasplysserarg
420425430
trpglnglnglyasnvalphesercysservalmethisglualaleu
435440445
hisasnhistyrthrglnlysserleuserleuserproglylys
450455460
<210>13
<211>236
<212>prt
<213>智人
<400>13
metaspmetargvalproalaglnleuleuglyleuleuleuleutrp
151015
leuargglyalaargcysaspileglnmetthrglnserproserser
202530
leuseralaservalglyaspargvalthrilethrcyslysalaser
354045
glnaspileasnlystyrvalalatrptyrglnglnlysproglylys
505560
alaprolysleuleuiletyrtyrthrsertrpleuglnproglyval
65707580
proserargpheserglyserglyserglythraspphethrphethr
859095
ileserserleuglnprogluaspilealathrtyrtyrcysleugln
100105110
tyraspasnleuleutyrthrpheglyglnglythrlysleugluile
115120125
lysargthrvalalaalaproservalpheilepheproproserasp
130135140
gluglnleulysserglythralaservalvalcysleuleuasnasn
145150155160
phetyrproargglualalysvalglntrplysvalaspasnalaleu
165170175
glnserglyasnserglngluservalthrgluglnaspserlysasp
180185190
serthrtyrserleuserserthrleuthrleuserlysalaasptyr
195200205
glulyshislysvaltyralacysgluvalthrhisglnglyleuser
210215220
serprovalthrlysserpheasnargglyglucys
225230235
<210>14
<211>467
<212>prt
<213>智人
<400>14
metaspmetargvalproalaglnleuleuglyleuleuleuleutrp
151015
leuargglyalaargcysgluvalglnleuvalgluserglyglygly
202530
leuvalglnproglyglyserleuargleusercysalaalasergly
354045
phethrpheserargtyrtrpmetasntrpvalargglnalaprogly
505560
lysglyleuglutrpvalalaglnileargleulysseraspasntyr
65707580
alathrhistyralagluservallysglyargphethrileserarg
859095
aspasnalalysasnserleutyrleuglnmetasnserleuargala
100105110
gluaspthralavaltyrtyrcysthrgluglyleuasptyrtrpgly
115120125
glnglythrthrvalthrvalserseralaserthrlysglyproser
130135140
valpheproleualaproserserlysserthrserglyglythrala
145150155160
alaleuglycysleuvallysasptyrpheprogluprovalthrval
165170175
sertrpasnserglyalaleuthrserglyvalhisthrpheproala
180185190
valleuglnserserglyleutyrserleuserservalvalthrval
195200205
proserserserleuglythrglnthrtyrilecysasnvalasnhis
210215220
lysproserasnthrlysvalasplyslysvalgluprolyssercys
225230235240
asplysthrhisthrcysproprocysproalaprogluleuleugly
245250255
glyproservalpheleupheproprolysprolysaspthrleumet
260265270
ileserargthrprogluvalthrcysvalvalvalaspvalserhis
275280285
gluaspprogluvallyspheasntrptyrvalaspglyvalgluval
290295300
hisasnalalysthrlysproargglugluglntyrasnserthrtyr
305310315320
argvalvalservalleuthrvalleuhisglnasptrpleuasngly
325330335
lysglutyrlyscyslysvalserasnlysalaleuproalaproile
340345350
glulysthrileserlysalalysglyglnproarggluproglnval
355360365
tyrthrleuproproserarggluglumetthrlysasnglnvalser
370375380
leuthrcysleuvallysglyphetyrproseraspilealavalglu
385390395400
trpgluserasnglyglnprogluasnasntyrlysthrthrpropro
405410415
valleuaspseraspglyserphepheleutyrserlysleuthrval
420425430
asplysserargtrpglnglnglyasnvalphesercysservalmet
435440445
hisglualaleuhisasnhistyrthrglnlysserleuserleuser
450455460
proglylys
465
<210>15
<211>236
<212>prt
<213>智人
<400>15
metaspmetargvalleualaglnleuleuglyleuleuleuleucys
151015
pheproglyalaargcysaspileglnmetthrglnserproserser
202530
leuseralaservalglyaspargvalthrilethrcysargalaser
354045
glnglyileserasntrpleualatrptyrglnglnlysproglulys
505560
alaprolysserleuiletyralaalaserserleuglnserglyval
65707580
proserargpheserglyserglyserglythraspphethrleuthr
859095
ileserserleuglnprogluaspphealathrtyrtyrcysglngln
100105110
tyraspsertyrproargthrpheglyglnglythrlysvalgluile
115120125
lysargthrvalalaalaproservalpheilepheproproserasp
130135140
gluglnleulysserglythralaservalvalcysleuleuasnasn
145150155160
phetyrproargglualalysvalglntrplysvalaspasnalaleu
165170175
glnserglyasnserglngluservalthrgluglnaspserlysasp
180185190
serthrtyrserleuserserthrleuthrleuserlysalaasptyr
195200205
glulyshislysvaltyralacysgluvalthrhisglnglyleuser
210215220
serprovalthrlysserpheasnargglyglucys
225230235
<210>16
<211>466
<212>prt
<213>智人
<400>16
metgluleuglyleuasntrpvalpheleuvalalaileleuglugly
151015
valhiscysgluvalglnleuvalgluserglyglyglyleuvalgln
202530
proglyglyserleuargleusercysalaalaserglyphethrphe
354045
sersertyrtrpmetsertrpvalargglnalaproglylysglyleu
505560
glutrpvalalatyrilelysglnaspglyasnglulystyrtyrval
65707580
aspservallysglyargphethrileserargaspasnalalysasn
859095
serleutyrleuglnmetasnserleuargalagluaspthralaval
100105110
tyrtyrcysalaarggluglyileleutrppheglyaspleuprothr
115120125
phetrpglyglnglythrleuvalthrvalserseralaserthrlys
130135140
glyproservalpheproleualaprocysserargserthrserglu
145150155160
serthralaalaleuglycysleuvallysasptyrpheproglupro
165170175
valthrvalsertrpasnserglyalaleuthrserglyvalhisthr
180185190
pheproalavalleuglnserserglyleutyrserleuserserval
195200205
valthrvalproserserasnpheglythrglnthrtyrthrcysasn
210215220
valasphislysproserasnthrlysvalasplysthrvalgluarg
225230235240
lyscyscysvalglucysproprocysproalaproprovalalagly
245250255
proservalpheleupheproprolysprolysaspthrleumetile
260265270
serargthrprogluvalthrcysvalvalvalaspvalserhisglu
275280285
aspprogluvalglnpheasntrptyrvalaspglyvalgluvalhis
290295300
asnalalysthrlysproargglugluglnpheasnserthrphearg
305310315320
valvalservalleuthrvalvalhisglnasptrpleuasnglylys
325330335
glutyrlyscyslysvalserasnlysglyleuproalaproileglu
340345350
lysthrileserlysthrlysglyglnproarggluproglnvaltyr
355360365
thrleuproproserarggluglumetthrlysasnglnvalserleu
370375380
thrcysleuvallysglyphetyrproseraspilealavalglutrp
385390395400
gluserasnglyglnprogluasnasntyrlysthrthrpropromet
405410415
leuaspseraspglyserphepheleutyrserlysleuthrvalasp
420425430
lysserargtrpglnglnglyasnvalphesercysservalmethis
435440445
glualaleuhisasnhistyrthrglnlysserleuserleuserpro
450455460
glylys
465
<210>17
<211>241
<212>prt
<213>智人
<400>17
metaspmetargleuproalaglnleuleuglyleuleumetleutrp
151015
valproglyserserglyaspvalleumetthrglnserproleuser
202530
leuprovalthrleuglyglnproalaserilesercysargserser
354045
glnserilevalhisserasnglyasnthrtyrleuglutrptyrleu
505560
glnargproglyglnserprolysleuleuiletyrlysvalserasn
65707580
argpheserglyvalproaspargpheserglyserglyserglythr
859095
aspphethrleulysileserargvalglualagluaspvalglyval
100105110
tyrtyrcyspheglnglyserhisvalproleuthrpheglyalagly
115120125
thrlysleugluilelysargthrvalalaalaproservalpheile
130135140
pheproproseraspgluglnleulysserglythralaservalval
145150155160
cysleuleuasnasnphetyrproargglualalysvalglntrplys
165170175
valaspasnalaleuglnserglyasnserglngluservalthrglu
180185190
glnaspserlysaspserthrtyrserleuserserthrleuthrleu
195200205
serlysalaasptyrglulyshislysvaltyralacysgluvalthr
210215220
hisglnglyleuserserprovalthrlysserpheasnargglyglu
225230235240
cys
<210>18
<211>470
<212>prt
<213>智人
<400>18
metaspthrleucysserthrleuleuleuleuthrileprosertrp
151015
valleuserglnvalthrleulysgluserglyproalaleuvallys
202530
prothrglnthrleuthrleuthrcysthrpheserglypheserleu
354045
argthrserglymetglyvalglytrpileargglnproproglylys
505560
alaleuglutrpleualahisiletrptrpaspaspasplyssertyr
65707580
asnproserleulysserglnleuthrileserlysaspthrserlys
859095
asnglnvalvalleuthrmetthrasnmetaspprovalaspthrala
100105110
thrtyrtyrcysalaargargasntyrtyrtyraspasptyrpheala
115120125
tyrtrpglyglnglythrleuvalthrvalserseralaserthrlys
130135140
glyproservalpheproleualaproserserlysserthrsergly
145150155160
glythralaalaleuglycysleuvallysasptyrpheproglupro
165170175
valthrvalsertrpasnserglyalaleuthrserglyvalhisthr
180185190
pheproalavalleuglnserserglyleutyrserleuserserval
195200205
valthrvalproserserserleuglythrglnthrtyrilecysasn
210215220
valasnhislysproserasnthrlysvalasplyslysvalglupro
225230235240
lyssercysasplysthrhisthrcysproprocysproalaproglu
245250255
leuleuglyglyproservalpheleupheproprolysprolysasp
260265270
thrleumetileserargthrprogluvalthrcysvalvalvalasp
275280285
valserhisgluaspprogluvallyspheasntrptyrvalaspgly
290295300
valgluvalhisasnalalysthrlysproargglugluglntyrasn
305310315320
serthrtyrargvalvalservalleuthrvalleuhisglnasptrp
325330335
leuasnglylysglutyrlyscyslysvalserasnlysalaleupro
340345350
alaproileglulysthrileserlysalalysglyglnproargglu
355360365
proglnvaltyrthrleuproproserargaspgluleuthrlysasn
370375380
glnvalserleuthrcysleuvallysglyphetyrproseraspile
385390395400
alavalglutrpgluserasnglyglnprogluasnasntyrlysthr
405410415
thrproprovalleuaspseraspglyserphepheleutyrserlys
420425430
leuthrvalasplysserargtrpglnglnglyasnvalphesercys
435440445
servalmethisglualaleuhisasnhistyrthrglnlysserleu
450455460
serleuserproglylys
465470
<210>19
<211>235
<212>prt
<213>智人
<400>19
metgluthrproalaglnleuleupheleuleuleuleutrpleupro
151015
aspthrthrglygluilevalleuthrglnserproglythrleuser
202530
leuserproglygluargalathrleusercysargalaserglnser
354045
valsersersertyrphealatrptyrglnglnlysproglyglnala
505560
proargleuleuiletyrglythrserserargalathrglyilepro
65707580
aspargpheserglyserglyserglythraspphethrleuthrval
859095
serargleugluprogluaspphealavaltyrtyrcysglnglntyr
100105110
aspargserproargthrpheglyglnglythrlysvalgluilelys
115120125
argthrvalalaalaproservalpheilepheproproseraspglu
130135140
glnleulysserglythralaservalvalcysleuleuasnasnphe
145150155160
tyrproargglualalysvalglntrplysvalaspasnalaleugln
165170175
serglyasnserglngluservalthrgluglnaspserlysaspser
180185190
thrtyrserleuserserthrleuthrleuserlysalaasptyrglu
195200205
lyshislysvaltyralacysgluvalthrhisglnglyleuserser
210215220
provalthrlysserpheasnargglyglucys
225230235
<210>20
<211>463
<212>prt
<213>智人
<400>20
metasptrpthrtrpargileleupheleuvalalaalaalathrgly
151015
alahisserglnvalglnleuvalglnserglyalaalavallyslys
202530
proglyalaservallysvalsercyslysalaserglytyrthrphe
354045
thrglytyrtyrilehistrpvalargglnalaproglyglnglyleu
505560
glutrpmetglytrpileasnproasnserglyglythrasntyrala
65707580
glnlyspheglnglyargvalthrmetthrargaspthrserileser
859095
thralasermetgluleuserargleuargseraspaspthralaval
100105110
tyrphecysalaargaspargtrpleuaspalapheaspiletrpgly
115120125
glnglythrmetvalthrvalserseralaserthrlysglyproser
130135140
valpheproleualaprocysserargserthrsergluserthrala
145150155160
alaleuglycysleuvallysasptyrpheprogluprovalthrval
165170175
sertrpasnserglyalaleuthrserglyvalhisthrpheproala
180185190
valleuglnserserglyleutyrserleuserservalvalthrval
195200205
proserserasnpheglythrglnthrtyrthrcysasnvalasphis
210215220
lysproserasnthrlysvalasplysthrvalgluarglyscyscys
225230235240
valglucysproprocysproalaproprovalalaglyproserval
245250255
pheleupheproprolysprolysaspthrleumetileserargthr
260265270
progluvalthrcysvalvalvalaspvalserhisgluaspproglu
275280285
valglnpheasntrptyrvalaspglyvalgluvalhisasnalalys
290295300
thrlysproargglugluglnpheasnserthrpheargvalvalser
305310315320
valleuthrvalvalhisglnasptrpleuasnglylysglutyrlys
325330335
cyslysvalserasnlysglyleuproalaproileglulysthrile
340345350
serlysthrlysglyglnproarggluproglnvaltyrthrleupro
355360365
proserarggluglumetthrlysasnglnvalserleuthrcysleu
370375380
vallysglyphetyrproseraspilealavalglutrpgluserasn
385390395400
glyglnprogluasnasntyrlysthrthrproprometleuaspser
405410415
aspglyserphepheleutyrserlysleuthrvalasplysserarg
420425430
trpglnglnglyasnvalphesercysservalmethisglualaleu
435440445
hisasnhistyrthrglnlysserleuserleuserproglylys
450455460
<210>21
<211>235
<212>prt
<213>智人
<400>21
metgluthrproalaglnleuleupheleuleuleuleutrpleupro
151015
aspthrthrglygluilevalleuthrglnserproglythrleuser
202530
leuserproglygluargalathrleusercysargalaserglnser
354045
valserserglytyrleuthrtrptyrglnglnlysproglyglnala
505560
proargleuleuiletyrglyalaserserargalathrglyilepro
65707580
aspargpheserglyserglyserglythraspphethrleuthrile
859095
serargleugluprogluaspphealavaltyrtyrcysglnglntyr
100105110
glyasnserleuserargpheglyglnglythrlysleugluilelys
115120125
argthrvalalaalaproservalpheilepheproproseraspglu
130135140
glnleulysserglythralaservalvalcysleuleuasnasnphe
145150155160
tyrproargglualalysvalglntrplysvalaspasnalaleugln
165170175
serglyasnserglngluservalthrgluglnaspserlysaspser
180185190
thrtyrserleuserserthrleuthrleuserlysalaasptyrglu
195200205
lyshislysvaltyralacysgluvalthrhisglnglyleuserser
210215220
provalthrlysserpheasnargglyglucys
225230235
<210>22
<211>474
<212>prt
<213>智人
<400>22
metaspmetargvalproalaglnleuleuglyleuleuleuleutrp
151015
leuargglyalaargcysglnvalglnleuvalgluserglyglygly
202530
valvalglnproglyargserleuargleusercysalaalasergly
354045
phethrphesersertyrglymethistrpvalargglnalaprogly
505560
lysglyleuglutrpvalalavaliletrptyraspglyserasnlys
65707580
tyrtyralaaspservallysglyargpheileileserargasplys
859095
serlysasnthrleutyrleuglnmetasnserleuargalagluasp
100105110
thralavaltyrtyrcysalaargalaglyglyilealaalaalagly
115120125
leutyrtyrtyrtyrglymetaspvaltrpglyglnglythrthrval
130135140
thrvalserseralaserthrlysglyproservalpheproleuala
145150155160
procysserargserthrsergluserthralaalaleuglycysleu
165170175
vallysasptyrpheprogluprovalthrvalsertrpasnsergly
180185190
alaleuthrserglyvalhisthrpheproalavalleuglnserser
195200205
glyleutyrserleuserservalvalthrvalproserserasnphe
210215220
glythrglnthrtyrthrcysasnvalasphislysproserasnthr
225230235240
lysvalasplysthrvalgluarglyscyscysvalglucyspropro
245250255
cysproalaproprovalalaglyproservalpheleuphepropro
260265270
lysprolysaspthrleumetileserargthrprogluvalthrcys
275280285
valvalvalaspvalserhisgluaspprogluvalglnpheasntrp
290295300
tyrvalaspglyvalgluvalhisasnalalysthrlysproargglu
305310315320
gluglnpheasnserthrpheargvalvalservalleuthrvalval
325330335
hisglnasptrpleuasnglylysglutyrlyscyslysvalserasn
340345350
lysglyleuproalaproileglulysthrileserlysthrlysgly
355360365
glnproarggluproglnvaltyrthrleuproproserarggluglu
370375380
metthrlysasnglnvalserleuthrcysleuvallysglyphetyr
385390395400
proseraspilealavalglutrpgluserasnglyglnprogluasn
405410415
asntyrlysthrthrproprometleuaspseraspglyserphephe
420425430
leutyrserlysleuthrvalasplysserargtrpglnglnglyasn
435440445
valphesercysservalmethisglualaleuhisasnhistyrthr
450455460
glnlysserleuserleuserproglylys
465470
<210>23
<211>236
<212>prt
<213>智人
<400>23
metaspmetargvalproalaglnleuleuglyleuleuleuleutrp
151015
leuargglyalaargcyssersergluleuthrglnaspprothrval
202530
servalalaleuglyglnthrvallysilethrcysglnglyaspser
354045
leuargserphetyralasertrptyrglnglnlysproglyglnala
505560
provalleuvalphetyrglylysasnasnargproserglyilepro
65707580
aspargpheserglyserserserglyasnthralaserleuthrile
859095
thrglyalaglnalagluaspglualaasptyrtyrcysasnserarg
100105110
aspserservaltyrhisleuvalleuglyglyglythrlysleuthr
115120125
valleuglyglnprolysalaasnprothrvalthrleuphepropro
130135140
serserglugluleuglnalaasnlysalathrleuvalcysleuile
145150155160
seraspphetyrproglyalavalthrvalalatrplysalaaspgly
165170175
serprovallysalaglyvalgluthrthrlysproserlysglnser
180185190
asnasnlystyralaalasersertyrleuserleuthrproglugln
195200205
trplysserhisargsertyrsercysglnvalthrhisgluglyser
210215220
thrvalglulysthrvalalaprothrglucysser
225230235
<210>24
<211>478
<212>prt
<213>智人
<400>24
metaspmetargvalproalaglnleuleuglyleuleuleuleutrp
151015
leuargglyalaargcysglnvalglnleuvalglnserglyalaglu
202530
vallyslysproglyalaservallysvalsercyslysalasergly
354045
tyrthrphethrglytyrtyrmethistrpvalargglnalaprogly
505560
glnglyleuglutrpmetglytrpileasnproasnserglyglythr
65707580
asntyralaglnlyspheglnglyargvalthrmetthrargaspthr
859095
serileserthralatyrmetgluleuserargleuargseraspasp
100105110
thralavaltyrphecysalaargaspglnmetserileilemetleu
115120125
argglyvalpheproprotyrtyrtyrglymetaspvaltrpglygln
130135140
glythrthrvalthrvalserseralaserthrlysglyproserval
145150155160
pheproleualaprocysserargserthrsergluserthralaala
165170175
leuglycysleuvallysasptyrpheprogluprovalthrvalser
180185190
trpasnserglyalaleuthrserglyvalhisthrpheproalaval
195200205
leuglnserserglyleutyrserleuserservalvalthrvalpro
210215220
serserasnpheglythrglnthrtyrthrcysasnvalasphislys
225230235240
proserasnthrlysvalasplysthrvalgluarglyscyscysval
245250255
glucysproprocysproalaproprovalalaglyproservalphe
260265270
leupheproprolysprolysaspthrleumetileserargthrpro
275280285
gluvalthrcysvalvalvalaspvalserhisgluaspprogluval
290295300
glnpheasntrptyrvalaspglyvalgluvalhisasnalalysthr
305310315320
lysproargglugluglnpheasnserthrpheargvalvalserval
325330335
leuthrvalvalhisglnasptrpleuasnglylysglutyrlyscys
340345350
lysvalserasnlysglyleuproalaproileglulysthrileser
355360365
lysthrlysglyglnproarggluproglnvaltyrthrleupropro
370375380
serarggluglumetthrlysasnglnvalserleuthrcysleuval
385390395400
lysglyphetyrproseraspilealavalglutrpgluserasngly
405410415
glnprogluasnasntyrlysthrthrproprometleuaspserasp
420425430
glyserphepheleutyrserlysleuthrvalasplysserargtrp
435440445
glnglnglyasnvalphesercysservalmethisglualaleuhis
450455460
asnhistyrthrglnlysserleuserleuserproglylys
465470475
<210>25
<211>241
<212>prt
<213>智人
<400>25
metaspmetargvalproalaglnleuleuglyleuleuleuleutrp
151015
leuargglyalaargcysaspilevalmetthrglnserproleuser
202530
leuprovalthrproglygluproalaserilesercysargserser
354045
glnserleuleuhisserasnglytyrasntyrleuasptrptyrleu
505560
glnlysproglyglnserproglnleuleuiletyrleuglyserasn
65707580
argalaserglyvalproaspargpheserglyserglyserglythr
859095
aspphethrleulysileserargvalglualagluaspvalglyval
100105110
tyrtyrcysmetglnalaleuglnthrproleuthrpheglyglygly
115120125
thrlysvalgluilelysargthrvalalaalaproservalpheile
130135140
pheproproseraspgluglnleulysserglythralaservalval
145150155160
cysleuleuasnasnphetyrproargglualalysvalglntrplys
165170175
valaspasnalaleuglnserglyasnserglngluservalthrglu
180185190
glnaspserlysaspserthrtyrserleuserserthrleuthrleu
195200205
serlysalaasptyrglulyshislysvaltyralacysgluvalthr
210215220
hisglnglyleuserserprovalthrlysserpheasnargglyglu
225230235240
cys
<210>26
<211>475
<212>prt
<213>智人
<400>26
metaspmetargvalproalaglnleuleuglyleuleuleuleutrp
151015
leuargglyalaargcysgluvalglnleuvalgluserglyglygly
202530
leuvalglnproglyglyserleuargleusercysalaalasergly
354045
phethrphesersertyrtrpmetsertrpvalargglnalaprogly
505560
lysglyleuglutrpvalalaserilelysglnaspglyserglulys
65707580
tyrtyrvalaspservallysglyargphethrileserargaspasn
859095
alaargasnserleutyrleuglnmetasnserleuargalagluasp
100105110
thralavaltyrtyrcysalaargaspleuvalleumetvaltyrasp
115120125
ileasptyrtyrtyrtyrglymetaspvaltrpglyglnglythrthr
130135140
valthrvalserseralaserthrlysglyproservalpheproleu
145150155160
alaprocysserargserthrsergluserthralaalaleuglycys
165170175
leuvallysasptyrpheprogluprovalthrvalsertrpasnser
180185190
glyalaleuthrserglyvalhisthrpheproalavalleuglnser
195200205
serglyleutyrserleuserservalvalthrvalproserserasn
210215220
pheglythrglnthrtyrthrcysasnvalasphislysproserasn
225230235240
thrlysvalasplysthrvalgluarglyscyscysvalglucyspro
245250255
procysproalaproprovalalaglyproservalpheleuphepro
260265270
prolysprolysaspthrleumetileserargthrprogluvalthr
275280285
cysvalvalvalaspvalserhisgluaspprogluvalglnpheasn
290295300
trptyrvalaspglyvalgluvalhisasnalalysthrlysproarg
305310315320
glugluglnpheasnserthrpheargvalvalservalleuthrval
325330335
valhisglnasptrpleuasnglylysglutyrlyscyslysvalser
340345350
asnlysglyleuproalaproileglulysthrileserlysthrlys
355360365
glyglnproarggluproglnvaltyrthrleuproproserargglu
370375380
glumetthrlysasnglnvalserleuthrcysleuvallysglyphe
385390395400
tyrproseraspilealavalglutrpgluserasnglyglnproglu
405410415
asnasntyrlysthrthrproprometleuaspseraspglyserphe
420425430
pheleutyrserlysleuthrvalasplysserargtrpglnglngly
435440445
asnvalphesercysservalmethisglualaleuhisasnhistyr
450455460
thrglnlysserleuserleuserproglylys
465470475
<210>27
<211>241
<212>prt
<213>智人
<400>27
metaspmetargvalproalaglnleuleuglyleuleuleuleutrp
151015
leuargglyalaargcysaspilevalmetthrglnserproleuser
202530
leuprovalthrproglygluproalaserilesercysargserser
354045
glnserleuleuhisserasnglytyrasntyrleuasptrptyrleu
505560
glnlysproglyglnserproglnleuleuiletyrleuglyserasn
65707580
argalaserglyvalproaspargpheserglyserglyserglythr
859095
hisleuthrleulysileserargvalglualagluaspvalglyval
100105110
tyrtyrcysmetglnthrleuglnthrproleuthrpheglyglygly
115120125
thrlysvalgluilelysargthrvalalaalaproservalpheile
130135140
pheproproseraspgluglnleulysserglythralaservalval
145150155160
cysleuleuasnasnphetyrproargglualalysvalglntrplys
165170175
valaspasnalaleuglnserglyasnserglngluservalthrglu
180185190
glnaspserlysaspserthrtyrserleuserserthrleuthrleu
195200205
serlysalaasptyrglulyshislysvaltyralacysgluvalthr
210215220
hisglnglyleuserserprovalthrlysserpheasnargglyglu
225230235240
cys
<210>28
<211>475
<212>prt
<213>智人
<400>28
metaspmetargvalproalaglnleuleuglyleuleuleuleutrp
151015
leuargglyalaargcysgluvalglnleuvalgluserglyglygly
202530
leuvalglnproglyglyserleuargleusercysalaalasergly
354045
phethrpheserasntyrtrpmetsertrpvalargglnalaprogly
505560
lysglyleuglutrpvalalaserilelysglnaspglyserglulys
65707580
tyrtyrvalaspservallysglyargphealaileserargaspasn
859095
alalysasnserleupheleuglnmetasnserleuargalagluasp
100105110
thralavaltyrtyrcysalaargaspleuvalleumetvaltyrasp
115120125
ileasptyrtyrtyrtyrglymetaspvaltrpglyglnglythrthr
130135140
valthrvalserseralaserthrlysglyproservalpheproleu
145150155160
alaprocysserargserthrsergluserthralaalaleuglycys
165170175
leuvallysasptyrpheprogluprovalthrvalsertrpasnser
180185190
glyalaleuthrserglyvalhisthrpheproalavalleuglnser
195200205
serglyleutyrserleuserservalvalthrvalproserserasn
210215220
pheglythrglnthrtyrthrcysasnvalasphislysproserasn
225230235240
thrlysvalasplysthrvalgluarglyscyscysvalglucyspro
245250255
procysproalaproprovalalaglyproservalpheleuphepro
260265270
prolysprolysaspthrleumetileserargthrprogluvalthr
275280285
cysvalvalvalaspvalserhisgluaspprogluvalglnpheasn
290295300
trptyrvalaspglyvalgluvalhisasnalalysthrlysproarg
305310315320
glugluglnpheasnserthrpheargvalvalservalleuthrval
325330335
valhisglnasptrpleuasnglylysglutyrlyscyslysvalser
340345350
asnlysglyleuproalaproileglulysthrileserlysthrlys
355360365
glyglnproarggluproglnvaltyrthrleuproproserargglu
370375380
glumetthrlysasnglnvalserleuthrcysleuvallysglyphe
385390395400
tyrproseraspilealavalglutrpgluserasnglyglnproglu
405410415
asnasntyrlysthrthrproprometleuaspseraspglyserphe
420425430
pheleutyrserlysleuthrvalasplysserargtrpglnglngly
435440445
asnvalphesercysservalmethisglualaleuhisasnhistyr
450455460
thrglnlysserleuserleuserproglylys
465470475
<210>29
<211>235
<212>prt
<213>智人
<400>29
metthrcysserproleuleuleuthrleuleuilehiscysthrgly
151015
sertrpalaglnservalleuthrglnproproservalseralaala
202530
proglyglnlysvalthrilesercysserglyserserserasnile
354045
glyasnasntyrvalsertrptyrglnglnleuproglythralapro
505560
lysleuleuiletyraspasnasnlysargproserglyileproasp
65707580
argpheserglyserlysserglythrserthrthrleuglyilethr
859095
glyleuglnthrglyaspglualaasptyrtyrcysglythrtrpasp
100105110
serargleuseralavalvalpheglyglyglythrlysleuthrval
115120125
leuglyglnprolysalaasnprothrvalthrleupheproproser
130135140
serglugluleuglnalaasnlysalathrleuvalcysleuileser
145150155160
aspphetyrproglyalavalthrvalalatrplysalaaspglyser
165170175
provallysalaglyvalgluthrthrlysproserlysglnserasn
180185190
asnlystyralaalasersertyrleuserleuthrprogluglntrp
195200205
lysserhisargsertyrsercysglnvalthrhisgluglyserthr
210215220
valglulysthrvalalaprothrglucysser
225230235
<210>30
<211>475
<212>prt
<213>智人
<400>30
metglupheglyleusertrpvalpheleuvalalaleuleuarggly
151015
valglncysglnvalglnleuvalgluserglyglyglyvalvalgln
202530
proglyargserleuargleusercysalaalaserglyphethrphe
354045
serserpheglymethistrpvalargglnalaproglylysglyleu
505560
glutrpvalalavalileserpheaspglyserilelystyrserval
65707580
aspservallysglyargphethrileserargaspasnserlysasn
859095
thrleupheleuglnmetasnserleuargalagluaspthralaval
100105110
tyrtyrcysalaargaspargleuasntyrtyraspserserglytyr
115120125
tyrhistyrlystyrtyrglymetalavaltrpglyglnglythrthr
130135140
valthrvalserseralaserthrlysglyproservalpheproleu
145150155160
alaprocysserargserthrsergluserthralaalaleuglycys
165170175
leuvallysasptyrpheprogluprovalthrvalsertrpasnser
180185190
glyalaleuthrserglyvalhisthrpheproalavalleuglnser
195200205
serglyleutyrserleuserservalvalthrvalproserserasn
210215220
pheglythrglnthrtyrthrcysasnvalasphislysproserasn
225230235240
thrlysvalasplysthrvalgluarglyscyscysvalglucyspro
245250255
procysproalaproprovalalaglyproservalpheleuphepro
260265270
prolysprolysaspthrleumetileserargthrprogluvalthr
275280285
cysvalvalvalaspvalserhisgluaspprogluvalglnpheasn
290295300
trptyrvalaspglyvalgluvalhisasnalalysthrlysproarg
305310315320
glugluglnpheasnserthrpheargvalvalservalleuthrval
325330335
valhisglnasptrpleuasnglylysglutyrlyscyslysvalser
340345350
asnlysglyleuproalaproileglulysthrileserlysthrlys
355360365
glyglnproarggluproglnvaltyrthrleuproproserargglu
370375380
glumetthrlysasnglnvalserleuthrcysleuvallysglyphe
385390395400
tyrproseraspilealavalglutrpgluserasnglyglnproglu
405410415
asnasntyrlysthrthrproprometleuaspseraspglyserphe
420425430
pheleutyrserlysleuthrvalasplysserargtrpglnglngly
435440445
asnvalphesercysservalmethisglualaleuhisasnhistyr
450455460
thrglnlysserleuserleuserproglylys
465470475
<210>31
<211>234
<212>prt
<213>智人
<400>31
metaspmetargvalproalaglnleuleuglyleuleuleuleutrp
151015
leuargglyalaargcystyrgluleuthrglnproproservalser
202530
valserproglyglnthralathrilethrcysserglyasplysleu
354045
glygluargtyralasertrptyrglnglnargproglyglnserpro
505560
valleuvaliletyrglnaspilelysargproserglyileproglu
65707580
argpheserglyserasnserglyasnthralathrleuthrileser
859095
glythrglnalametaspglualaasptyrphecysglnalatrptyr
100105110
serserthrasnvalleupheglyglyglythrlysleuthrvalleu
115120125
glyglnprolysalaalaproservalthrleupheproproserser
130135140
glugluleuglnalaasnlysalathrleuvalcysleuileserasp
145150155160
phetyrproglyalavalthrvalalatrplysalaaspserserpro
165170175
vallysalaglyvalgluthrthrthrproserlysglnserasnasn
180185190
lystyralaalasersertyrleuserleuthrprogluglntrplys
195200205
serhisargsertyrsercysglnvalthrhisgluglyserthrval
210215220
glulysthrvalalaprothrglucysser
225230
<210>32
<211>466
<212>prt
<213>智人
<400>32
metglupheglyleusertrpvalpheleuvalalaleuleuarggly
151015
valglncysglnvalglnleuvalgluserglyglyglyvalvalgln
202530
proglyargserleuargleusercysalaalaserglyphethrphe
354045
sersertyrglymethistrpvalargglnalaproglylysglyleu
505560
glutrpvalalavaliletrptyralagluserasnlystyrtyrala
65707580
aspservallysglyargphethrileserargaspasnserlysasn
859095
thrleutyrleuglnmetasnserleuargalagluaspthralaval
100105110
tyrtyrcysalaargalaglngluglyilealaproaspalapheasp
115120125
iletrpglyglnglythrmetvalthrvalserseralaserthrlys
130135140
glyproservalpheproleualaprocysserargserthrserglu
145150155160
serthralaalaleuglycysleuvallysasptyrpheproglupro
165170175
valthrvalsertrpasnserglyalaleuthrserglyvalhisthr
180185190
pheproalavalleuglnserserglyleutyrserleuserserval
195200205
valthrvalproserserasnpheglythrglnthrtyrthrcysasn
210215220
valasphislysproserasnthrlysvalasplysthrvalgluarg
225230235240
lyscyscysvalglucysproprocysproalaproprovalalagly
245250255
proservalpheleupheproprolysprolysaspthrleumetile
260265270
serargthrprogluvalthrcysvalvalvalaspvalserhisglu
275280285
aspprogluvalglnpheasntrptyrvalaspglyvalgluvalhis
290295300
asnalalysthrlysproargglugluglnpheasnserthrphearg
305310315320
valvalservalleuthrvalvalhisglnasptrpleuasnglylys
325330335
glutyrlyscyslysvalserasnlysglyleuproalaproileglu
340345350
lysthrileserlysthrlysglyglnproarggluproglnvaltyr
355360365
thrleuproproserarggluglumetthrlysasnglnvalserleu
370375380
thrcysleuvallysglyphetyrproseraspilealavalglutrp
385390395400
gluserasnglyglnprogluasnasntyrlysthrthrpropromet
405410415
leuaspseraspglyserphepheleutyrserlysleuthrvalasp
420425430
lysserargtrpglnglnglyasnvalphesercysservalmethis
435440445
glualaleuhisasnhistyrthrglnlysserleuserleuserpro
450455460
glylys
465
<210>33
<211>234
<212>prt
<213>智人
<400>33
metglyserthralaileleuglyleuleuleualavalleuglngly
151015
glyargalagluilevalleuthrglnserproglythrleuserleu
202530
serproglygluargalathrleusercysargalaserglnserval
354045
sersersertyrleualatrphisglnglnlysproglyglnalapro
505560
argleuleuiletyrglyalaserserargalathrglyileproasp
65707580
argpheserglyserglyserglythraspphethrleuthrileser
859095
argleugluprogluaspphealavaltyrtyrcysglnglntyrgly
100105110
serserprotrpthrpheglyglnglythrlysvalgluilelysarg
115120125
thrvalalaalaproservalpheilepheproproseraspglugln
130135140
leulysserglythralaservalvalcysleuleuasnasnphetyr
145150155160
proargglualalysvalglntrplysvalaspasnalaleuglnser
165170175
glyasnserglngluservalthrgluglnaspserlysaspserthr
180185190
tyrserleuserserthrleuthrleuserlysalaasptyrglulys
195200205
hislysvaltyralacysgluvalthrhisglnglyleuserserpro
210215220
valthrlysserpheasnargglyglucys
225230
<210>34
<211>463
<212>prt
<213>智人
<400>34
metglyserthralaileleuglyleuleuleualavalleuglngly
151015
glyargalagluvalglnleuleugluserglyglyglyleuvalgln
202530
proglyglyserleuargleusercysalaalaserglyphethrphe
354045
serthrtyrvalmetsertrpvalargglnalaproglylysglyleu
505560
glutrpvalserserileserglyserglyleuglysertyrtyrala
65707580
aspservallysglyargphethrileserargaspasnserlysasn
859095
thrleutyrleuglnmetasnserleuargalagluaspthralaval
100105110
tyrtyrcysalalysglualahisargglypropheasptyrtrpgly
115120125
glnglythrleuvalthrvalserseralaserthrlysglyproser
130135140
valpheproleualaprocysserargserthrsergluserthrala
145150155160
alaleuglycysleuvallysasptyrpheprogluprovalthrval
165170175
sertrpasnserglyalaleuthrserglyvalhisthrpheproala
180185190
valleuglnserserglyleutyrserleuserservalvalthrval
195200205
proserserasnpheglythrglnthrtyrthrcysasnvalasphis
210215220
lysproserasnthrlysvalasplysthrvalgluarglyscyscys
225230235240
valglucysproprocysproalaproprovalalaglyproserval
245250255
pheleupheproprolysprolysaspthrleumetileserargthr
260265270
progluvalthrcysvalvalvalaspvalserhisgluaspproglu
275280285
valglnpheasntrptyrvalaspglyvalgluvalhisasnalalys
290295300
thrlysproargglugluglnpheasnserthrpheargvalvalser
305310315320
valleuthrvalvalhisglnasptrpleuasnglylysglutyrlys
325330335
cyslysvalserasnlysglyleuproalaproileglulysthrile
340345350
serlysthrlysglyglnproarggluproglnvaltyrthrleupro
355360365
proserarggluglumetthrlysasnglnvalserleuthrcysleu
370375380
vallysglyphetyrproseraspilealavalglutrpgluserasn
385390395400
glyglnprogluasnasntyrlysthrthrproprometleuaspser
405410415
aspglyserphepheleutyrserlysleuthrvalasplysserarg
420425430
trpglnglnglyasnvalphesercysservalmethisglualaleu
435440445
hisasnhistyrthrglnlysserleuserleuserproglylys
450455460
<210>35
<211>239
<212>prt
<213>智人
<400>35
metargleuleualaglnleuleuglyleuleumetleutrpvalpro
151015
glyserserglyaspilevalmetthrglnthrproleuserserpro
202530
valthrleuglyglnproalaserilesercysargserserglnser
354045
leuvalhisseraspglyasnthrtyrleusertrpleuglnglnarg
505560
proglyglnproproargleuleuiletyrlyslyspheasnargphe
65707580
serglyvalproaspargpheserglyserglyalaglythraspphe
859095
thrleulysileserargvalglualagluaspvalglyvaltyrtyr
100105110
cysmetglnalathrglnileproleuthrpheglyproglythrlys
115120125
valaspilelysargthrvalalaalaproservalpheilephepro
130135140
proseraspgluglnleulysserglythralaservalvalcysleu
145150155160
leuasnasnphetyrproargglualalysvalglntrplysvalasp
165170175
asnalaleuglnserglyasnserglngluservalthrgluglnasp
180185190
serlysaspserthrtyrserleuserserthrleuthrleuserlys
195200205
alaasptyrglulyshislysvaltyralacysgluvalthrhisgln
210215220
glyleuserserprovalthrlysserpheasnargglyglucys
225230235
<210>36
<211>472
<212>prt
<213>智人
<400>36
metglupheglyleusertrpvalpheleuvalalaleuleuarggly
151015
valglncysglnvalglnleuvalgluserglyglyglyvalvalgln
202530
proglyargserleuargleusercysalaalaserglyphethrphe
354045
serphetyrglymethistrpvalargglnalaproglylysglyleu
505560
glutrpvalalavaliletrptyraspglyserasnlystyrtyrala
65707580
aspservallysglyargphethrileserargaspasnserlysasn
859095
thrleutyrleuglnmetasnserleuargalagluaspthralaval
100105110
tyrtyrcysalaargglyglytyrasptyrvaltrpglysertyrarg
115120125
argasnserasppheasptyrtrpglyglnglythrleuvalthrval
130135140
serseralaserthrlysglyproservalpheproleualaprocys
145150155160
serargserthrsergluserthralaalaleuglycysleuvallys
165170175
asptyrpheprogluprovalthrvalsertrpasnserglyalaleu
180185190
thrserglyvalhisthrpheproalavalleuglnserserglyleu
195200205
tyrserleuserservalvalthrvalproserserasnpheglythr
210215220
glnthrtyrthrcysasnvalasphislysproserasnthrlysval
225230235240
asplysthrvalgluarglyscyscysvalglucysproprocyspro
245250255
alaproprovalalaglyproservalpheleupheproprolyspro
260265270
lysaspthrleumetileserargthrprogluvalthrcysvalval
275280285
valaspvalserhisgluaspprogluvalglnpheasntrptyrval
290295300
aspglyvalgluvalhisasnalalysthrlysproarggluglugln
305310315320
pheasnserthrpheargvalvalservalleuthrvalvalhisgln
325330335
asptrpleuasnglylysglutyrlyscyslysvalserasnlysgly
340345350
leuproalaproileglulysthrileserlysthrlysglyglnpro
355360365
arggluproglnvaltyrthrleuproproserarggluglumetthr
370375380
lysasnglnvalserleuthrcysleuvallysglyphetyrproser
385390395400
aspilealavalglutrpgluserasnglyglnprogluasnasntyr
405410415
lysthrthrproprometleuaspseraspglyserphepheleutyr
420425430
serlysleuthrvalasplysserargtrpglnglnglyasnvalphe
435440445
sercysservalmethisglualaleuhisasnhistyrthrglnlys
450455460
serleuserleuserproglylys
465470
<210>37
<211>235
<212>prt
<213>智人
<400>37
metglualaproalaglnleuleupheleuleuleuleutrpleupro
151015
aspthrthrglygluilevalmetthrglnserproalathrleuser
202530
valserproglygluargalathrleusercysargalaserglnser
354045
valaspserasnleualatrptyrargglnlysproglyglnalapro
505560
argleuleuiletyrglyalaserthrargalathrglyileproala
65707580
argpheserglyserglyserglythrgluphethrleuthrileser
859095
serleuglnsergluaspphealavaltyrtyrcysglnglntyrile
100105110
asntrpproproilethrpheglyglnglythrargleugluilelys
115120125
argthrvalalaalaproservalpheilepheproproseraspglu
130135140
glnleulysserglythralaservalvalcysleuleuasnasnphe
145150155160
tyrproargglualalysvalglntrplysvalaspasnalaleugln
165170175
serglyasnserglngluservalthrgluglnaspserlysaspser
180185190
thrtyrserleuserserthrleuthrleuserlysalaasptyrglu
195200205
lyshislysvaltyralacysgluvalthrhisglnglyleuserser
210215220
provalthrlysserpheasnargglyglucys
225230235
<210>38
<211>465
<212>prt
<213>智人
<400>38
metlyshisleutrpphepheleuleuleuvalalaalaproargtrp
151015
valleuserglnvalglnleuglngluserglyproglyleuvallys
202530
prosergluthrleuserleuthrcysthrvalserglyglyserile
354045
seriletyrtyrtrpsertrpileargglnproproglylysglyleu
505560
glutrpileglytyrvaltyrtyrserglyserthrasntyrasnpro
65707580
serleulysserargvalthrileservalaspthrserlysasngln
859095
pheserleulysleuasnservalthralaalaaspthralavaltyr
100105110
tyrcysalaargglyglytyraspphetrpserglytyrpheasptyr
115120125
trpglyglnglythrleuvalthrvalserseralaserthrlysgly
130135140
proservalpheproleualaprocysserargserthrsergluser
145150155160
thralaalaleuglycysleuvallysasptyrpheprogluproval
165170175
thrvalsertrpasnserglyalaleuthrserglyvalhisthrphe
180185190
proalavalleuglnserserglyleutyrserleuserservalval
195200205
thrvalproserserasnpheglythrglnthrtyrthrcysasnval
210215220
asphislysproserasnthrlysvalasplysthrvalgluarglys
225230235240
cyscysvalglucysproprocysproalaproprovalalaglypro
245250255
servalpheleupheproprolysprolysaspthrleumetileser
260265270
argthrprogluvalthrcysvalvalvalaspvalserhisgluasp
275280285
progluvalglnpheasntrptyrvalaspglyvalgluvalhisasn
290295300
alalysthrlysproargglugluglnpheasnserthrpheargval
305310315320
valservalleuthrvalvalhisglnasptrpleuasnglylysglu
325330335
tyrlyscyslysvalserasnlysglyleuproalaproileglulys
340345350
thrileserlysthrlysglyglnproarggluproglnvaltyrthr
355360365
leuproproserarggluglumetthrlysasnglnvalserleuthr
370375380
cysleuvallysglyphetyrproseraspilealavalglutrpglu
385390395400
serasnglyglnprogluasnasntyrlysthrthrproprometleu
405410415
aspseraspglyserphepheleutyrserlysleuthrvalasplys
420425430
serargtrpglnglnglyasnvalphesercysservalmethisglu
435440445
alaleuhisasnhistyrthrglnlysserleuserleuserprogly
450455460
lys
465
<210>39
<211>240
<212>prt
<213>智人
<400>39
metvalleuglnthrglnvalpheileserleuleuleutrpileser
151015
glyalatyrglyaspilevalleuthrglnserproaspserleuala
202530
valserleuglygluargalathrileasncyslysserserglnser
354045
ileleutyrserserserasngluasnpheleuthrtrptyrglngln
505560
lysproglyglnproprolysleuleuiletyrtrpalaserthrarg
65707580
gluserglyvalproaspargpheserglyserglyserglythrasp
859095
phethrleuthrileserserleuglnprogluaspvalalavaltyr
100105110
tyrcysglnglntyrpheservalpheargthrpheglyglnglythr
115120125
argvalgluilelysargthrvalalaalaproservalpheilephe
130135140
proproseraspgluglnleulysserglythralaservalvalcys
145150155160
leuleuasnasnphetyrproargglualalysvalglntrplysval
165170175
aspasnalaleuglnserglyasnserglngluservalthrglugln
180185190
aspserlysaspserthrtyrserleuserserthrleuthrleuser
195200205
lysalaasptyrglulyshislysvaltyralacysgluvalthrhis
210215220
glnglyleuserserprovalthrlysserpheasnargglyglucys
225230235240
<210>40
<211>465
<212>prt
<213>智人
<400>40
metasptrpthrtrpargileleupheleuvalalaalaalathrgly
151015
alahisserglnvalglnleuvalglnserglyalagluvallyslys
202530
proglyalaservallysvalsercyslysalaserglytyrthrphe
354045
thrglytyrtyrilehistrpvalargglnalaproglyglnglyleu
505560
glutrpmetglytrpileasnproasnserglyglythrasnserala
65707580
glnlyspheargglyargvalthrmetthrargaspthrserileser
859095
thralatyrmetgluleuserargleuargseraspaspthralaval
100105110
tyrtyrcysalaarggluglyglytyrsertyrglytyrpheasptyr
115120125
trpglyglnglythrleuvalthrvalserseralaserthrlysgly
130135140
proservalpheproleualaprocysserargserthrsergluser
145150155160
thralaalaleuglycysleuvallysasptyrpheprogluproval
165170175
thrvalsertrpasnserglyalaleuthrserglyvalhisthrphe
180185190
proalavalleuglnserserglyleutyrserleuserservalval
195200205
thrvalproserserasnpheglythrglnthrtyrthrcysasnval
210215220
asphislysproserasnthrlysvalasplysthrvalgluarglys
225230235240
cyscysvalglucysproprocysproalaproprovalalaglypro
245250255
servalpheleupheproprolysprolysaspthrleumetileser
260265270
argthrprogluvalthrcysvalvalvalaspvalserhisgluasp
275280285
progluvalglnpheasntrptyrvalaspglyvalgluvalhisasn
290295300
alalysthrlysproargglugluglnpheasnserthrpheargval
305310315320
valservalleuthrvalvalhisglnasptrpleuasnglylysglu
325330335
tyrlyscyslysvalserasnlysglyleuproalaproileglulys
340345350
thrileserlysthrlysglyglnproarggluproglnvaltyrthr
355360365
leuproproserarggluglumetthrlysasnglnvalserleuthr
370375380
cysleuvallysglyphetyrproseraspilealavalglutrpglu
385390395400
serasnglyglnprogluasnasntyrlysthrthrproprometleu
405410415
aspseraspglyserphepheleutyrserlysleuthrvalasplys
420425430
serargtrpglnglnglyasnvalphesercysservalmethisglu
435440445
alaleuhisasnhistyrthrglnlysserleuserleuserprogly
450455460
lys
465
<210>41
<211>236
<212>prt
<213>智人
<400>41
metaspmetargvalproalaglnleuleuglyleuleuleuleutrp
151015
pheproglyalaargcysaspileglnmetthrglnserproserser
202530
leuseralaservalglyaspargvalthrilethrcysargalaser
354045
glnglyileargasnaspleuglytrptyrglnglnlysproglylys
505560
alaprolysargleuiletyralaalaserserleuglnserglyval
65707580
proserargpheserglyserglyserglythrgluphethrleuthr
859095
ileserservalglnprogluaspphevalthrtyrtyrcysleugln
100105110
hisasnserasnproleuthrpheglyglyglythrlysvalgluile
115120125
lysargthrvalalaalaproservalpheilepheproproserasp
130135140
gluglnleulysserglythralaservalvalcysleuleuasnasn
145150155160
phetyrproargglualalysvalglntrplysvalaspasnalaleu
165170175
glnserglyasnserglngluservalthrgluglnaspserlysasp
180185190
serthrtyrserleuserserthrleuthrleuserlysalaasptyr
195200205
glulyshislysvaltyralacysgluvalthrhisglnglyleuser
210215220
serprovalthrlysserpheasnargglyglucys
225230235
<210>42
<211>473
<212>prt
<213>智人
<400>42
metglupheglyleusertrpvalpheleuvalalaleuleuarggly
151015
valglncysglnvalglnleuvalgluserglyglyglyvalvalgln
202530
proglyargserleuargleusercysalaalaserglyphethrphe
354045
sersertyrglymethistrpvalargglnalaproglylysglyleu
505560
glutrpvalalavalmettrptyraspglyserasnlysasptyrval
65707580
aspservallysglyargphethrileserargaspasnserlysasn
859095
thrleutyrleuglnmetasnargleuargalagluaspthralaval
100105110
tyrtyrcysalaargglulysasphistyraspileleuthrglytyr
115120125
asntyrtyrtyrglyleuaspvaltrpglyglnglythrthrvalthr
130135140
valserseralaserthrlysglyproservalpheproleualapro
145150155160
cysserargserthrsergluserthralaalaleuglycysleuval
165170175
lysasptyrpheprogluprovalthrvalsertrpasnserglyala
180185190
leuthrserglyvalhisthrpheproalavalleuglnsersergly
195200205
leutyrserleuserservalvalthrvalproserserasnphegly
210215220
thrglnthrtyrthrcysasnvalasphislysproserasnthrlys
225230235240
valasplysthrvalgluarglyscyscysvalglucysproprocys
245250255
proalaproprovalalaglyproservalpheleupheproprolys
260265270
prolysaspthrleumetileserargthrprogluvalthrcysval
275280285
valvalaspvalserhisgluaspprogluvalglnpheasntrptyr
290295300
valaspglyvalgluvalhisasnalalysthrlysproarggluglu
305310315320
glnpheasnserthrpheargvalvalservalleuthrvalvalhis
325330335
glnasptrpleuasnglylysglutyrlyscyslysvalserasnlys
340345350
glyleuproalaproileglulysthrileserlysthrlysglygln
355360365
proarggluproglnvaltyrthrleuproproserarggluglumet
370375380
thrlysasnglnvalserleuthrcysleuvallysglyphetyrpro
385390395400
seraspilealavalglutrpgluserasnglyglnprogluasnasn
405410415
tyrlysthrthrproprometleuaspseraspglyserphepheleu
420425430
tyrserlysleuthrvalasplysserargtrpglnglnglyasnval
435440445
phesercysservalmethisglualaleuhisasnhistyrthrgln
450455460
lysserleuserleuserproglylys
465470
<210>43
<211>235
<212>prt
<213>智人
<400>43
metgluthrproalaglnleuleupheleuleuleuleutrpleupro
151015
aspthrthrglygluilevalleuthrglnserproglythrleuser
202530
leuserproglygluargalathrleusercysargalaserglntyr
354045
ileserasnthrtyrleualatrppheglnglnlysproglyglnala
505560
proargleuleuiletyrglyalaalathrargalathrglyilepro
65707580
aspargpheserglyserglyserglythraspphethrphethrile
859095
serargleugluprogluaspphealavaltyrtyrcysglnglntyr
100105110
glyserserprotrpthrpheglyglnglythrthrvalgluilelys
115120125
argthrvalalaalaproservalpheilepheproproseraspglu
130135140
glnleulysserglythralaservalvalcysleuleuasnasnphe
145150155160
tyrproargglualalysvalglntrplysvalaspasnalaleugln
165170175
serglyasnserglngluservalthrgluglnaspserlysaspser
180185190
thrtyrserleuserserthrleuthrleuserlysalaasptyrglu
195200205
lyshislysvaltyralacysgluvalthrhisglnglyleuserser
210215220
provalthrlysserpheasnargglyglucys
225230235
<210>44
<211>463
<212>prt
<213>智人
<400>44
metasptrpthrtrpargileleupheleuvalalaalaalathrgly
151015
alahisserglnvalglnleuvalglnserglyalagluvallyslys
202530
proglyalaservallysvalsercyslysalaserglytyrthrphe
354045
thrglytyrtyrmethistrpvalargglnalaproglyglnglyleu
505560
glutrpmetglytrpileasnproasnserglyglythrasntyrala
65707580
glnargpheargglyargvalthrmetthrargaspthrserileser
859095
thralatyrmetgluleuserargleuargseraspaspthralaval
100105110
tyrtyrcysalaargalaprotyrasptrpthrpheasptyrtrpgly
115120125
glnglythrleuvalthrvalserseralaserthrlysglyproser
130135140
valpheproleualaprocysserargserthrsergluserthrala
145150155160
alaleuglycysleuvallysasptyrpheprogluprovalthrval
165170175
sertrpasnserglyalaleuthrserglyvalhisthrpheproala
180185190
valleuglnserserglyleutyrserleuserservalvalthrval
195200205
proserserasnpheglythrglnthrtyrthrcysasnvalasphis
210215220
lysproserasnthrlysvalasplysthrvalgluarglyscyscys
225230235240
valglucysproprocysproalaproprovalalaglyproserval
245250255
pheleupheproprolysprolysaspthrleumetileserargthr
260265270
progluvalthrcysvalvalvalaspvalserhisgluaspproglu
275280285
valglnpheasntrptyrvalaspglyvalgluvalhisasnalalys
290295300
thrlysproargglugluglnpheasnserthrpheargvalvalser
305310315320
valleuthrvalvalhisglnasptrpleuasnglylysglutyrlys
325330335
cyslysvalserasnlysglyleuproalaproileglulysthrile
340345350
serlysthrlysglyglnproarggluproglnvaltyrthrleupro
355360365
proserarggluglumetthrlysasnglnvalserleuthrcysleu
370375380
vallysglyphetyrproseraspilealavalglutrpgluserasn
385390395400
glyglnprogluasnasntyrlysthrthrproprometleuaspser
405410415
aspglyserphepheleutyrserlysleuthrvalasplysserarg
420425430
trpglnglnglyasnvalphesercysservalmethisglualaleu
435440445
hisasnhistyrthrglnlysserleuserleuserproglylys
450455460
<210>45
<211>236
<212>prt
<213>智人
<400>45
metaspmetargvalproalaglnleuleuglyleuleuleuleutrp
151015
leuargglyalaargcysaspileglnmetthrglnserproserser
202530
valseralaservalglyaspargvalthrilethrcysargalaser
354045
glnglyileserasntrpleualatrptyrglnglnlysproglythr
505560
alaprolysleuleuiletyralaalaserserleuglnserglyval
65707580
proserargpheserglyserglyserglythraspphethrleuthr
859095
ileserserleuglnprogluaspphealathrtyrtyrcysglngln
100105110
alaasnserpheprophethrpheglyproglythrlysvalaspile
115120125
lysargthrvalalaalaproservalpheilepheproproserasp
130135140
gluglnleulysserglythralaservalvalcysleuleuasnasn
145150155160
phetyrproargglualalysvalglntrplysvalaspasnalaleu
165170175
glnserglyasnserglngluservalthrgluglnaspserlysasp
180185190
serthrtyrserleuserserthrleuthrleuserlysalaasptyr
195200205
glulyshislysvaltyralacysgluvalthrhisglnglyleuser
210215220
serprovalthrlysserpheasnargglyglucys
225230235
<210>46
<211>469
<212>prt
<213>智人
<400>46
metaspmetargvalproalaglnleuleuglyleuleuleuleutrp
151015
leuargglyalaargcysglnvalglnleuvalglnserglythrglu
202530
vallyslysproglyalasermetlysvalsercyslysalasergly
354045
tyrthrphethrsertyrtyrmethistrpvalargglnalaprogly
505560
glnglyleuglutrpmetglyileileasnproserglyaspserthr
65707580
sertyralaglnlyspheglnglyargvalthrmetthrargaspthr
859095
serthrasnthrvaltyrmetgluleuserserleuargsergluasp
100105110
thralamettyrtyrcysalaargaspvalgluvalargglyileser
115120125
hispheasptyrtrpglyglnglythrleuvalthrvalserserala
130135140
serthrlysglyproservalpheproleualaprocysserargser
145150155160
thrsergluserthralaalaleuglycysleuvallysasptyrphe
165170175
progluprovalthrvalsertrpasnserglyalaleuthrsergly
180185190
valhisthrpheproalavalleuglnserserglyleutyrserleu
195200205
serservalvalthrvalproserserasnpheglythrglnthrtyr
210215220
thrcysasnvalasphislysproserasnthrlysvalasplysthr
225230235240
valgluarglyscyscysvalglucysproprocysproalapropro
245250255
valalaglyproservalpheleupheproprolysprolysaspthr
260265270
leumetileserargthrprogluvalthrcysvalvalvalaspval
275280285
serhisgluaspprogluvalglnpheasntrptyrvalaspglyval
290295300
gluvalhisasnalalysthrlysproargglugluglnpheasnser
305310315320
thrpheargvalvalservalleuthrvalvalhisglnasptrpleu
325330335
asnglylysglutyrlyscyslysvalserasnlysglyleuproala
340345350
proileglulysthrileserlysthrlysglyglnproargglupro
355360365
glnvaltyrthrleuproproserarggluglumetthrlysasngln
370375380
valserleuthrcysleuvallysglyphetyrproseraspileala
385390395400
valglutrpgluserasnglyglnprogluasnasntyrlysthrthr
405410415
proprometleuaspseraspglyserphepheleutyrserlysleu
420425430
thrvalasplysserargtrpglnglnglyasnvalphesercysser
435440445
valmethisglualaleuhisasnhistyrthrglnlysserleuser
450455460
leuserproglylys
465
<210>47
<211>238
<212>prt
<213>智人
<400>47
metglytrpsercysileileleupheleuvalalathralathrgly
151015
valhisseraspileglnleuthrglnserproserserleuserala
202530
servalglyaspargvalthrmetsercyslysserserglnserval
354045
leutyrseralaasnhislysasntyrleualatrptyrglnglnlys
505560
proglylysalaprolysleuleuiletyrtrpalaserthrargglu
65707580
serglyvalproserargpheserglyserglyserglythraspphe
859095
thrphethrileserserleuglnprogluaspilealathrtyrtyr
100105110
cyshisglntyrleusersertrpthrpheglyglyglythrlysval
115120125
glnilelysargthrvalalaalaproservalpheilephepropro
130135140
seraspgluglnleulysserglythralaservalvalcysleuleu
145150155160
asnasnphetyrproargglualalysvalglntrplysvalaspasn
165170175
alaleuglnserglyasnserglngluservalthrgluglnaspser
180185190
lysaspserthrtyrserleuserserthrleuthrleuserlysala
195200205
asptyrglulyshislysvaltyralacysgluvalthrhisglngly
210215220
leuserserprovalthrlysserpheasnargglyglucys
225230235
<210>48
<211>465
<212>prt
<213>智人
<400>48
metglytrpsercysileileleupheleuvalalathralathrgly
151015
valhisserglnvalglnleuvalglnserglyalagluvallyslys
202530
proglyserservallysvalsercyslysalaserglytyrthrphe
354045
thrsertyrtrpleuhistrpvalargglnalaproglyglnglyleu
505560
glutrpileglytyrileasnproargasnasptyrthrglutyrasn
65707580
glnasnphelysasplysalathrilethralaaspgluserthrasn
859095
thralatyrmetgluleuserserleuargsergluaspthralaphe
100105110
tyrphecysalaargargaspilethrthrphetyrtrpglyglngly
115120125
thrthrvalthrvalserseralaserthrlysglyproservalphe
130135140
proleualaproserserlysserthrserglyglythralaalaleu
145150155160
glycysleuvallysasptyrpheprogluprovalthrvalsertrp
165170175
asnserglyalaleuthrserglyvalhisthrpheproalavalleu
180185190
glnserserglyleutyrserleuserservalvalthrvalproser
195200205
serserleuglythrglnthrtyrilecysasnvalasnhislyspro
210215220
serasnthrlysvalasplysargvalgluprolyssercysasplys
225230235240
thrhisthrcysproprocysproalaprogluleuleuglyglypro
245250255
servalpheleupheproprolysprolysaspthrleumetileser
260265270
argthrprogluvalthrcysvalvalvalaspvalserhisgluasp
275280285
progluvallyspheasntrptyrvalaspglyvalgluvalhisasn
290295300
alalysthrlysproargglugluglntyrasnserthrtyrargval
305310315320
valservalleuthrvalleuhisglnasptrpleuasnglylysglu
325330335
tyrlyscyslysvalserasnlysalaleuproalaproileglulys
340345350
thrileserlysalalysglyglnproarggluproglnvaltyrthr
355360365
leuproproserarggluglumetthrlysasnglnvalserleuthr
370375380
cysleuvallysglyphetyrproseraspilealavalglutrpglu
385390395400
serasnglyglnprogluasnasntyrlysthrthrproprovalleu
405410415
aspseraspglyserphepheleutyrserlysleuthrvalasplys
420425430
serargtrpglnglnglyasnvalphesercysservalmethisglu
435440445
alaleuhisasnhistyrthrglnlysserleuserleuserprogly
450455460
lys
465
<210>49
<211>235
<212>prt
<213>智人
<400>49
metgluthrproalaglnleuleupheleuleuleuleutrpleupro
151015
aspthrthrglygluilevalleuthrglnserproglythrleuser
202530
leuserproglygluargalathrleusercysargalaserglnser
354045
valsersersertyrleualatrptyrglnglnlysproglyglnala
505560
proargleuleuiletyrglyalaserserargalathrglyilepro
65707580
aspargpheserglyserglyserglythraspphethrleuthrile
859095
serargleugluprogluaspphealavaltyrtyrcysglnargser
100105110
glyglyserserphethrpheglyproglythrlysvalaspilelys
115120125
argthrvalalaalaproservalpheilepheproproseraspglu
130135140
glnleulysserglythralaservalvalcysleuleuasnasnphe
145150155160
tyrproargglualalysvalglntrplysvalaspasnalaleugln
165170175
serglyasnserglngluservalthrgluglnaspserlysaspser
180185190
thrtyrserleuserserthrleuthrleuserlysalaasptyrglu
195200205
lyshislysvaltyralacysgluvalthrhisglnglyleuserser
210215220
provalthrlysserpheasnargglyglucys
225230235
<210>50
<211>466
<212>prt
<213>智人
<400>50
metglyserthralaileleualaleuleuleualavalleuglngly
151015
valcysalagluvalglnleuvalglnserglyalagluvallyslys
202530
proglygluserleulysilesercyslysglyserglytyrasnphe
354045
thrsertyrtrpileglytrpvalargglnmetproglylysglyleu
505560
gluleumetglyileiletyrproglyaspseraspthrargtyrser
65707580
proserpheglnglyglnvalthrileseralaasplysserileser
859095
thralatyrleuglntrpserserleulysalaseraspthralamet
100105110
tyrtyrcysglyserglysertyrphetyrpheaspleutrpglyarg
115120125
glythrleuvalthrvalserseralaserthrlysglyproserval
130135140
pheproleualaproserserlysserthrserglyglythralaala
145150155160
leuglycysleuvallysasptyrpheprogluprovalthrvalser
165170175
trpasnserglyalaleuthrserglyvalhisthrpheproalaval
180185190
leuglnserserglyleutyrserleuserservalvalthrvalpro
195200205
serserserleuglythrglnthrtyrilecysasnvalasnhislys
210215220
proserasnthrlysvalasplyslysvalgluprolyssercysasp
225230235240
lysthrhisthrcysproprocysproalaprogluleuleuglygly
245250255
proservalpheleupheproprolysprolysaspthrleumetile
260265270
serargthrprogluvalthrcysvalvalvalaspvalserhisglu
275280285
aspprogluvallyspheasntrptyrvalaspglyvalgluvalhis
290295300
asnalalysthrlysproargglugluglntyrasnserthrtyrarg
305310315320
valvalservalleuthrvalleuhisglnasptrpleuasnglylys
325330335
glutyrlyscyslysvalserasnlysalaleuproalaproileglu
340345350
lysthrileserlysalalysglyglnproarggluproglnvaltyr
355360365
thrleuproproserargaspgluleuthrlysasnglnvalserleu
370375380
thrcysleuvallysglyphetyrproseraspilealavalglutrp
385390395400
gluserasnglyglnprogluasnasntyrlysthrthrproproval
405410415
leuaspseraspglyserphepheleutyrserlysleuthrvalasp
420425430
lysserargtrpglnglnglyasnvalphesercysservalmethis
435440445
glualaleuhisasnhistyrthrglnlysserleuserleuserpro
450455460
glylys
465
<210>51
<211>241
<212>prt
<213>智人
<400>51
metaspmetargvalproalaglnleuleuglyleuleuleuleutrp
151015
leuargglyalaargcysaspilevalmetthrglnserproleuser
202530
leuprovalthrproglygluproalaserilesercysargserser
354045
glnserleuleuhisserhisglytyrasntyrleuasptrptyrleu
505560
glnlysproglyglnserproglnleuleuiletyrleuglyserasn
65707580
argalaserglyvalproaspargpheserglyserglyserglythr
859095
aspphethrleulysileserargvalglualagluaspvalglyval
100105110
tyrtyrcysmetglnglythrhistrpproprothrpheglyglngly
115120125
thrlysleugluilelysargthrvalalaalaproservalpheile
130135140
pheproproseraspgluglnleulysserglythralaservalval
145150155160
cysleuleuasnasnphetyrproargglualalysvalglntrplys
165170175
valaspasnalaleuglnserglyasnserglngluservalthrglu
180185190
glnaspserlysaspserthrtyrserleuserserthrleuthrleu
195200205
serlysalaasptyrglulyshislysvaltyralacysgluvalthr
210215220
hisglnglyleuserserprovalthrlysserpheasnargglyglu
225230235240
cys
<210>52
<211>470
<212>prt
<213>智人
<400>52
metaspmetargvalproalaglnleuleuglyleuleuleuleutrp
151015
leuargglyalaargcysgluvalglnleuvalglnserglyglygly
202530
valvalglnproglyargserleuargleusercysalaalasergly
354045
phethrphesersertyrglymethistrpvalargglnalaprogly
505560
lysglyleuglutrpvalsertyrileserserserglyserthrile
65707580
tyrtyralaaspservallysglyargphethrileserargaspasn
859095
alalysasnserleutyrleuglnmetasnserleuargalagluasp
100105110
thralavaltyrtyrcysalaargaspleuleuasptyraspleuleu
115120125
thrglytyrglytyrtrpglyglnglythrleuvalthrvalserser
130135140
alaserthrlysglyproservalpheproleualaprocysserarg
145150155160
serthrsergluserthralaalaleuglycysleuvallysasptyr
165170175
pheprogluprovalthrvalsertrpasnserglyalaleuthrser
180185190
glyvalhisthrpheproalavalleuglnserserglyleutyrser
195200205
leuserservalvalthrvalproserserasnpheglythrglnthr
210215220
tyrthrcysasnvalasphislysproserasnthrlysvalasplys
225230235240
thrvalgluarglyscyscysvalglucysproprocysproalapro
245250255
provalalaglyproservalpheleupheproprolysprolysasp
260265270
thrleumetileserargthrprogluvalthrcysvalvalvalasp
275280285
valserhisgluaspprogluvalglnpheasntrptyrvalaspgly
290295300
valgluvalhisasnalalysthrlysproargglugluglnpheasn
305310315320
serthrpheargvalvalservalleuthrvalvalhisglnasptrp
325330335
leuasnglylysglutyrlyscyslysvalserasnlysglyleupro
340345350
alaproileglulysthrileserlysthrlysglyglnproargglu
355360365
proglnvaltyrthrleuproproserarggluglumetthrlysasn
370375380
glnvalserleuthrcysleuvallysglyphetyrproseraspile
385390395400
alavalglutrpgluserasnglyglnprogluasnasntyrlysthr
405410415
thrproprometleuaspseraspglyserphepheleutyrserlys
420425430
leuthrvalasplysserargtrpglnglnglyasnvalphesercys
435440445
servalmethisglualaleuhisasnhistyrthrglnlysserleu
450455460
serleuserproglylys
465470
<210>53
<211>235
<212>prt
<213>智人
<400>53
metgluthrproalaglnleuleupheleuleuleuleutrpleupro
151015
aspthrthrglygluilevalleuthrglnserproglythrleuser
202530
leuserproglygluargalathrleusercysargalaserglngly
354045
ileserargsertyrleualatrptyrglnglnlysproglyglnala
505560
proserleuleuiletyrglyalaserserargalathrglyilepro
65707580
aspargpheserglyserglyserglythraspphethrleuthrile
859095
serargleugluprogluaspphealavaltyrtyrcysglnglnphe
100105110
glyserserprotrpthrpheglyglnglythrlysvalgluilelys
115120125
argthrvalalaalaproservalpheilepheproproseraspglu
130135140
glnleulysserglythralaservalvalcysleuleuasnasnphe
145150155160
tyrproargglualalysvalglntrplysvalaspasnalaleugln
165170175
serglyasnserglngluservalthrgluglnaspserlysaspser
180185190
thrtyrserleuserserthrleuthrleuserlysalaasptyrglu
195200205
lyshislysvaltyralacysgluvalthrhisglnglyleuserser
210215220
provalthrlysserpheasnargglyglucys
225230235
<210>54
<211>471
<212>prt
<213>智人
<400>54
metlyshisleutrpphepheleuleuleuvalalaalaproargtrp
151015
valleuserglnvalglnleuglngluserglyproglyleuvallys
202530
proserglnthrleuserleuthrcysthrvalserglyglyserile
354045
serserglyasptyrphetrpsertrpileargglnleuproglylys
505560
glyleuglutrpileglyhisilehisasnserglythrthrtyrtyr
65707580
asnproserleulysserargvalthrileservalaspthrserlys
859095
lysglnpheserleuargleuserservalthralaalaaspthrala
100105110
valtyrtyrcysalaargaspargglyglyasptyrtyrtyrglymet
115120125
aspvaltrpglyglnglythrthrvalthrvalserseralaserthr
130135140
lysglyproservalpheproleualaproserserlysserthrser
145150155160
glyglythralaalaleuglycysleuvallysasptyrpheproglu
165170175
provalthrvalsertrpasnserglyalaleuthrserglyvalhis
180185190
thrpheproalavalleuglnserserglyleutyrserleuserser
195200205
valvalthrvalproserserserleuglythrglnthrtyrilecys
210215220
asnvalasnhislysproserasnthrlysvalasplysargvalglu
225230235240
prolyssercysasplysthrhisthrcysproprocysproalapro
245250255
gluleuleuglyglyproservalpheleupheproprolysprolys
260265270
aspthrleumetileserargthrprogluvalthrcysvalvalval
275280285
aspvalserhisgluaspprogluvallyspheasntrptyrvalasp
290295300
glyvalgluvalhisasnalalysthrlysproargglugluglntyr
305310315320
asnserthrtyrargvalvalservalleuthrvalleuhisglnasp
325330335
trpleuasnglylysglutyrlyscyslysvalserasnlysalaleu
340345350
proalaproileglulysthrileserlysalalysglyglnproarg
355360365
gluproglnvaltyrthrleuproproserarggluglumetthrlys
370375380
asnglnvalserleuthrcysleuvallysglyphetyrproserasp
385390395400
ilealavalglutrpgluserasnglyglnprogluasnasntyrlys
405410415
thrthrproprovalleuaspseraspglyserphepheleutyrser
420425430
lysleuthrvalasplysserargtrpglnglnglyasnvalpheser
435440445
cysservalmethisglualaleuhisasnhistyrthrglnlysser
450455460
leuserleuserproglylys
465470
<210>55
<211>236
<212>prt
<213>智人
<400>55
metaspmetargvalproalaglnleuleuglyleuleuleuleutrp
151015
leuserglyalaargcysaspileglnmetthrglnserproserser
202530
leuseralaservalglyaspargvalthrilethrcysglnalaser
354045
glnaspileserasntyrleuasntrptyrglnglnlysproglylys
505560
alaprolysleuleuiletyraspalaserasnleugluthrglyval
65707580
proserargpheserglyserglyserglythraspphethrphethr
859095
ileserserleuglnprogluaspilealathrtyrphecysglnhis
100105110
pheasphisleuproleualapheglyglyglythrlysvalgluile
115120125
lysargthrvalalaalaproservalpheilepheproproserasp
130135140
gluglnleulysserglythralaservalvalcysleuleuasnasn
145150155160
phetyrproargglualalysvalglntrplysvalaspasnalaleu
165170175
glnserglyasnserglngluservalthrgluglnaspserlysasp
180185190
serthrtyrserleuserserthrleuthrleuserlysalaasptyr
195200205
glulyshislysvaltyralacysgluvalthrhisglnglyleuser
210215220
serprovalthrlysserpheasnargglyglucys
225230235
<210>56
<211>464
<212>prt
<213>智人
<400>56
metlyshisleutrpphepheleuleuleuvalalaalaproargtrp
151015
valleuserglnvalglnleuglngluserglyproglyleuvallys
202530
prosergluthrleuserleuthrcysthrvalserglyglyserval
354045
serserglyasptyrtyrtrpthrtrpileargglnserproglylys
505560
glyleuglutrpileglyhisiletyrtyrserglyasnthrasntyr
65707580
asnproserleulysserargleuthrileserileaspthrserlys
859095
thrglnpheserleulysleuserservalthralaalaaspthrala
100105110
iletyrtyrcysvalargaspargvalthrglyalapheaspiletrp
115120125
glyglnglythrmetvalthrvalserseralaserthrlysglypro
130135140
servalpheproleualaprocysserargserthrsergluserthr
145150155160
alaalaleuglycysleuvallysasptyrpheprogluprovalthr
165170175
valsertrpasnserglyalaleuthrserglyvalhisthrphepro
180185190
alavalleuglnserserglyleutyrserleuserservalvalthr
195200205
valproserserasnpheglythrglnthrtyrthrcysasnvalasp
210215220
hislysproserasnthrlysvalasplysthrvalgluarglyscys
225230235240
cysvalglucysproprocysproalaproprovalalaglyproser
245250255
valpheleupheproprolysprolysaspthrleumetileserarg
260265270
thrprogluvalthrcysvalvalvalaspvalserhisgluasppro
275280285
gluvalglnpheasntrptyrvalaspglyvalgluvalhisasnala
290295300
lysthrlysproargglugluglnpheasnserthrpheargvalval
305310315320
servalleuthrvalvalhisglnasptrpleuasnglylysglutyr
325330335
lyscyslysvalserasnlysglyleuproalaproileglulysthr
340345350
ileserlysthrlysglyglnproarggluproglnvaltyrthrleu
355360365
proproserarggluglumetthrlysasnglnvalserleuthrcys
370375380
leuvallysglyphetyrproseraspilealavalglutrpgluser
385390395400
asnglyglnprogluasnasntyrlysthrthrproprometleuasp
405410415
seraspglyserphepheleutyrserlysleuthrvalasplysser
420425430
argtrpglnglnglyasnvalphesercysservalmethisgluala
435440445
leuhisasnhistyrthrglnlysserleuserleuserproglylys
450455460
<210>57
<211>236
<212>prt
<213>智人
<400>57
metgluthrproalaglnleuleupheleuleuleuleutrpleupro
151015
aspthralasergluilevalleuthrglnserproglythrleuser
202530
leuserproglygluargalathrleusercysargalaserglnser
354045
valserasnsertyrleualatrptyrglnglnlysproglyglnala
505560
proargleuleuiletyrglyalaserserargalaproglyilepro
65707580
aspargpheserglyserglyserglythraspphethrleuthrile
859095
serargleugluprogluaspphealavaltyrtyrcysglnglntyr
100105110
asphisseralaglytrpthrpheglyglnglythrlysvalgluile
115120125
lysargthrvalalaalaproservalpheilepheproproserasp
130135140
gluglnleulysserglythralaservalvalcysleuleuasnasn
145150155160
phetyrproargglualalysvalglntrplysvalaspasnalaleu
165170175
glnserglyasnserglngluservalthrgluglnaspserlysasp
180185190
serthrtyrserleuserserthrleuthrleuserlysalaasptyr
195200205
glulyshislysvaltyralacysgluvalthrhisglnglyleuser
210215220
serprovalthrlysserpheasnargglyglucys
225230235
<210>58
<211>460
<212>prt
<213>智人
<400>58
metglyserthralaileleuglyleuleuleualavalleuglngly
151015
valalasergluvalglnleuvalgluserglyglyglyleuvalgln
202530
proglyglyserleuargleusercysalaalaserglyphethrphe
354045
serargasnalametphetrpvalargglnalaproglylysglyleu
505560
glutrpvalserglyileglythrglyglyalathrsertyralaasp
65707580
servallysglyargphethrileserargaspasnalalysasnser
859095
leutyrleuglnmetasnserleuargalagluaspthralavaltyr
100105110
tyrcysalaargglyargtyrtyrpheprotrptrpglyglnglythr
115120125
leuvalthrvalserseralaserthrlysglyproservalphepro
130135140
leualaprocysserargserthrsergluserthralaalaleugly
145150155160
cysleuvallysasptyrpheprogluprovalthrvalsertrpasn
165170175
serglyalaleuthrserglyvalhisthrpheproalavalleugln
180185190
serserglyleutyrserleuserservalvalthrvalproserser
195200205
asnpheglythrglnthrtyrthrcysasnvalasphislysproser
210215220
asnthrlysvalasplysthrvalgluarglyscyscysvalglucys
225230235240
proprocysproalaproprovalalaglyproservalpheleuphe
245250255
proprolysprolysaspthrleumetileserargthrprogluval
260265270
thrcysvalvalvalaspvalserhisgluaspprogluvalglnphe
275280285
asntrptyrvalaspglyvalgluvalhisasnalalysthrlyspro
290295300
argglugluglnpheasnserthrpheargvalvalservalleuthr
305310315320
valvalhisglnasptrpleuasnglylysglutyrlyscyslysval
325330335
serasnlysglyleuproalaproileglulysthrileserlysthr
340345350
lysglyglnproarggluproglnvaltyrthrleuproproserarg
355360365
gluglumetthrlysasnglnvalserleuthrcysleuvallysgly
370375380
phetyrproseraspilealavalglutrpgluserasnglyglnpro
385390395400
gluasnasntyrlysthrthrproprometleuaspseraspglyser
405410415
phepheleutyrserlysleuthrvalasplysserargtrpglngln
420425430
glyasnvalphesercysservalmethisglualaleuhisasnhis
435440445
tyrthrglnlysserleuserleuserproglylys
450455460
<210>59
<211>234
<212>prt
<213>智人
<400>59
metgluthrproalaglnleuleupheleuleuleuleutrpleupro
151015
aspthrthrglygluilevalleuthrglnserproglythrleuser
202530
leuserproglygluargalathrleusercysargalaserglnser
354045
valsersersertyrleualatrptyrglnglnlysproglyglnala
505560
proargleuleuiletyrglyalaserargargalathrglyilepro
65707580
aspargpheserglyserglyserglythraspphethrleuthrile
859095
serargleugluprogluaspphealavaltyrtyrcysglnargtyr
100105110
glyserserhisthrpheglyglnglythrlysleugluileserarg
115120125
thrvalalaalaproservalpheilepheproproseraspglugln
130135140
leulysserglythralaservalvalcysleuleuasnasnphetyr
145150155160
proargglualalysvalglntrplysvalaspasnalaleuglnser
165170175
glyasnserglngluservalthrgluglnaspserlysaspserthr
180185190
tyrserleuserserthrleuthrleuserlysalaasptyrglulys
195200205
hislysvaltyralacysgluvalthrhisglnglyleuserserpro
210215220
valthrlysserpheasnargglyglucys
225230
<210>60
<211>467
<212>prt
<213>智人
<400>60
metglyserthralaileleualaleuleuleualavalleuglngly
151015
valcysalagluvalglnleuvalglnserglyalagluvallyslys
202530
proglygluserleulysilesercyslysvalserglytyrphephe
354045
thrthrtyrtrpileglytrpvalargglnmetproglylysglyleu
505560
glutyrmetglyileiletyrproglyaspseraspthrargtyrser
65707580
proserpheglnglyglnvalthrileseralaasplysserileser
859095
thralatyrleuglntrpserserleulysalaseraspthralamet
100105110
tyrtyrcysalaargglyglyasntrpasncyspheasptyrtrpgly
115120125
glnglythrleuvalthrvalserseralaserthrlysglyproser
130135140
valpheproleualaproserserlysserthrserglyglythrala
145150155160
alaleuglycysleuvallysasptyrpheprogluprovalthrval
165170175
sertrpasnserglyalaleuthrserglyvalhisthrpheproala
180185190
valleuglnserserglyleutyrserleuserservalvalthrval
195200205
proserserserleuglythrglnthrtyrilecysasnvalasnhis
210215220
lysproserasnthrlysvalasplysargvalgluprolyssercys
225230235240
asplysthrhisthrcysproprocysproalaprogluleuleugly
245250255
glyproservalpheleupheproprolysprolysaspthrleumet
260265270
ileserargthrprogluvalthrcysvalvalvalaspvalserhis
275280285
gluaspprogluvallyspheasntrptyrvalaspglyvalgluval
290295300
hisasnalalysthrlysproargglugluglntyrasnserthrtyr
305310315320
argvalvalservalleuthrvalleuhisglnasptrpleuasngly
325330335
lysglutyrlyscyslysvalserasnlysalaleuproalaproile
340345350
glulysthrileserlysalalysglyglnproarggluproglnval
355360365
tyrthrleuproproserargaspgluleuthrlysasnglnvalser
370375380
leuthrcysleuvallysglyphetyrproseraspilealavalglu
385390395400
trpgluserasnglyglnprogluasnasntyrlysthrthrpropro
405410415
valleuaspseraspglyserphepheleutyrserlysleuthrval
420425430
asplysserargtrpglnglnglyasnvalphesercysservalmet
435440445
hisglualaleuhisasnhistyrthrglnlysserleuserleuser
450455460
proglylys
465
<210>61
<211>241
<212>prt
<213>智人
<400>61
metaspmetargvalproalaglnleuleuglyleuleuleuleutrp
151015
leuargglyalaargcysaspvalvalmetthrglnserproleuser
202530
leuprovalthrproglygluproalaserilesercysargserser
354045
glnserleuleuhisserasnglytyrasntyrleuasptrptyrleu
505560
glnlysproglyglnserproglnleuleuiletyrleuglyserasn
65707580
argalaserglyvalproaspargpheserglyserglyserglythr
859095
aspphethrleulysileserargvalglualagluaspvalglyval
100105110
tyrtyrcysmetglnglythrhistrpproleuthrpheglyglngly
115120125
thrlysvalgluilelysargthrvalalaalaproservalpheile
130135140
pheproproseraspgluglnleulysserglythralaservalval
145150155160
cysleuleuasnasnphetyrproargglualalysvalglntrplys
165170175
valaspasnalaleuglnserglyasnserglngluservalthrglu
180185190
glnaspserlysaspserthrtyrserleuserserthrleuthrleu
195200205
serlysalaasptyrglulyshislysvaltyralacysgluvalthr
210215220
hisglnglyleuserserprovalthrlysserpheasnargglyglu
225230235240
cys
<210>62
<211>471
<212>prt
<213>智人
<400>62
metaspmetargvalproalaglnleuleuglyleuleuleuleutrp
151015
leuargglyalaargcysglnvalglnleuglngluserglyprogly
202530
leuvallysproserglythrleuserleuthrcysalavalsergly
354045
glyserileserserserasntrptrpsertrpvalargglnpropro
505560
glylysglyleuglutrpileglygluiletyrhisserglyserthr
65707580
asntyrasnproserleulysserargvalthrileservalasplys
859095
serlysasnglnpheserleulysleuserservalthralaalaasp
100105110
thralavaltyrtyrcysalaargtrpthrglyargthraspalaphe
115120125
aspiletrpglyglnglythrmetvalthrvalserseralaserthr
130135140
lysglyproservalpheproleualaproserserlysserthrser
145150155160
glyglythralaalaleuglycysleuvallysasptyrpheproglu
165170175
provalthrvalsertrpasnserglyalaleuthrserglyvalhis
180185190
thrpheproalavalleuglnserserglyleutyrserleuserser
195200205
valvalthrvalproserserserleuglythrglnthrtyrilecys
210215220
asnvalasnhislysproserasnthrlysvalasplyslysvalglu
225230235240
prolyssercysasplysthrhisthrcysproprocysproalapro
245250255
gluleuleuglyglyproservalpheleupheproprolysprolys
260265270
aspthrleumetileserargthrprogluvalthrcysvalvalval
275280285
aspvalserhisgluaspprogluvallyspheasntrptyrvalasp
290295300
glyvalgluvalhisasnalalysthrlysproargglugluglntyr
305310315320
asnserthrtyrargvalvalservalleuthrvalleuhisglnasp
325330335
trpleuasnglylysglutyrlyscyslysvalserasnlysalaleu
340345350
proalaproileglulysthrileserlysalalysglyglnproarg
355360365
gluproglnvaltyrthrleuproproserargaspgluleuthrlys
370375380
asnglnvalserleuthrcysleuvallysglyphetyrproserasp
385390395400
ilealavalglutrpgluserasnglyglnprogluasnasntyrlys
405410415
thrthrproprovalleuaspseraspglyserphepheleutyrser
420425430
lysleuthrvalasplysserargtrpglnglnglyasnvalpheser
435440445
cysservalmethisglualaleuhisasnhistyrthrglnlysser
450455460
leuserleuserproglylys
465470
<210>63
<211>234
<212>prt
<213>智人
<400>63
metglualaproalaglnleuleupheleuleuleuleutrpleupro
151015
aspthrthrglygluilevalmetthrglnserproalathrleuser
202530
valserproglygluargalathrleusercysargalaserglnser
354045
valserserasnleualatrppheglnglnlysproglyglnalapro
505560
argproleuiletyraspalaserthrargalathrglyvalproala
65707580
argpheserglyserglyserglythraspphethrleuthrileser
859095
serleuglnsergluaspphealavaltyrtyrcysglnglntyrasp
100105110
asntrpproleuthrpheglyglyglythrlysvalgluilelysarg
115120125
thrvalalaalaproservalpheilepheproproseraspglugln
130135140
leulysserglythralaservalvalcysleuleuasnasnphetyr
145150155160
proargglualalysvalglntrplysvalaspasnalaleuglnser
165170175
glyasnserglngluservalthrgluglnaspserlysaspserthr
180185190
tyrserleuserserthrleuthrleuserlysalaasptyrglulys
195200205
hislysvaltyralacysgluvalthrhisglnglyleuserserpro
210215220
valthrlysserpheasnargglyglucys
225230
<210>64
<211>461
<212>prt
<213>智人
<400>64
metglutrpthrtrpargvalleupheleuvalalaalaalathrgly
151015
alahisserglnvalglnleuvalglnserglyalagluvallyslys
202530
proglyalaservallysvalsercyslysalaserglytyrthrphe
354045
thrargtyrglyilesertrpvalargglnalaproglyglnglyleu
505560
glutrpmetglytrpileserthrtyrserglyasnthrasntyrala
65707580
glnlysleuglnglyargvalthrmetthrthraspthrserthrser
859095
thralatyrmetgluleuargserleuargseraspaspthralaval
100105110
tyrtyrcysalaargargglnleutyrpheasptyrtrpglyglngly
115120125
thrleuvalthrvalserseralaserthrlysglyproservalphe
130135140
proleualaprocysserargserthrsergluserthralaalaleu
145150155160
glycysleuvallysasptyrpheprogluprovalthrvalsertrp
165170175
asnserglyalaleuthrserglyvalhisthrpheproalavalleu
180185190
glnserserglyleutyrserleuserservalvalthrvalproser
195200205
serasnpheglythrglnthrtyrthrcysasnvalasphislyspro
210215220
serasnthrlysvalasplysthrvalgluarglyscyscysvalglu
225230235240
cysproprocysproalaproprovalalaglyproservalpheleu
245250255
pheproprolysprolysaspthrleumetileserargthrproglu
260265270
valthrcysvalvalvalaspvalserhisgluaspprogluvalgln
275280285
pheasntrptyrvalaspglyvalgluvalhisasnalalysthrlys
290295300
proargglugluglnpheasnserthrpheargvalvalservalleu
305310315320
thrvalvalhisglnasptrpleuasnglylysglutyrlyscyslys
325330335
valserasnlysglyleuproalaproileglulysthrileserlys
340345350
thrlysglyglnproarggluproglnvaltyrthrleuproproser
355360365
arggluglumetthrlysasnglnvalserleuthrcysleuvallys
370375380
glyphetyrproseraspilealavalglutrpgluserasnglygln
385390395400
progluasnasntyrlysthrthrproprometleuaspseraspgly
405410415
serphepheleutyrserlysleuthrvalasplysserargtrpgln
420425430
glnglyasnvalphesercysservalmethisglualaleuhisasn
435440445
histyrthrglnlysserleuserleuserproglylys
450455460
<210>65
<211>239
<212>prt
<213>智人
<400>65
metargleuproalaglnleuleuglyleuleumetleutrpilepro
151015
glyserseralaaspilevalmetthrglnthrproleuserleuser
202530
valthrproglyglnproalaserilesercyslysserglyglnser
354045
leuleuhisseraspglylysthrtyrleutyrtrptyrleuglnlys
505560
proglyglnproproglnpheleuiletyrgluvalserasnargphe
65707580
serargvalproaspargpheserglyserglyserglythraspphe
859095
thrleuargileserargvalglualagluaspvalglyiletyrtyr
100105110
cysmetglnserileglnleuprotrpthrpheglyglnglythrgln
115120125
valgluilelysargthrvalalaalaproservalpheilephepro
130135140
proseraspgluglnleulysserglythralaservalvalcysleu
145150155160
leuasnasnphetyrproargglualalysvalglntrplysvalasp
165170175
asnalaleuglnserglyasnserglngluservalthrgluglnasp
180185190
serlysaspserthrtyrserleuserserthrleuthrleuserlys
195200205
alaasptyrglulyshislysvaltyralacysgluvalthrhisgln
210215220
glyleuserserprovalthrlysserpheasnargglyglucys
225230235
<210>66
<211>459
<212>prt
<213>智人
<400>66
metglupheglyleusertrpvalpheleuvalalaleuleuarggly
151015
valglncysglnvalglnleuvalgluserglyglyglyvalvalgln
202530
proglyargserleuargleusercysalaalaserglyphethrphe
354045
serglytyrglymethistrpvalargglnalaproglylysglyleu
505560
glutrpvalalavalilesertyraspglyasnasplystyrtyrala
65707580
aspservallysglyargphethrileserargaspasnalalysasn
859095
thrleutyrleuglnmetasnserleuargalagluaspthralaval
100105110
tyrtyrcysalaarggluleuargvalleutrpglyglnglythrleu
115120125
valthrvalserseralaserthrlysglyproservalpheproleu
130135140
alaprocysserargserthrsergluserthralaalaleuglycys
145150155160
leuvallysasptyrpheprogluprovalthrvalsertrpasnser
165170175
glyalaleuthrserglyvalhisthrpheproalavalleuglnser
180185190
serglyleutyrserleuserservalvalthrvalproserserasn
195200205
pheglythrglnthrtyrthrcysasnvalasphislysproserasn
210215220
thrlysvalasplysthrvalgluarglyscyscysvalglucyspro
225230235240
procysproalaproprovalalaglyproservalpheleuphepro
245250255
prolysprolysaspthrleumetileserargthrprogluvalthr
260265270
cysvalvalvalaspvalserhisgluaspprogluvalglnpheasn
275280285
trptyrvalaspglyvalgluvalhisasnalalysthrlysproarg
290295300
glugluglnpheasnserthrpheargvalvalservalleuthrval
305310315320
valhisglnasptrpleuasnglylysglutyrlyscyslysvalser
325330335
asnlysglyleuproalaproileglulysthrileserlysthrlys
340345350
glyglnproarggluproglnvaltyrthrleuproproserargglu
355360365
glumetthrlysasnglnvalserleuthrcysleuvallysglyphe
370375380
tyrproseraspilealavalglutrpgluserasnglyglnproglu
385390395400
asnasntyrlysthrthrproprometleuaspseraspglyserphe
405410415
pheleutyrserlysleuthrvalasplysserargtrpglnglngly
420425430
asnvalphesercysservalmethisglualaleuhisasnhistyr
435440445
thrglnlysserleuserleuserproglylys
450455
<210>67
<211>235
<212>prt
<213>智人
<400>67
metaspmetargvalproalaglnleuleuglyleuleuleuleutrp
151015
leuargglyalaargcysaspileglnmetthrglnserproserser
202530
leuseralaservalglyaspargvalthrilethrcysargalaser
354045
glnaspilesersertyrleuasntrptyrglnglnlysproglylys
505560
alaprolysleuleuiletyrserthrserargleuasnserglyval
65707580
proserargpheserglyserglyserglythraspphethrleuthr
859095
ileserserleuglnprogluaspphealathrtyrtyrcysglngln
100105110
aspilelyshisprothrpheglyglnglythrlysvalgluilelys
115120125
argthrvalalaalaproservalpheilepheproproseraspglu
130135140
glnleulysserglythralaservalvalcysleuleuasnasnphe
145150155160
tyrproargglualalysvalglntrplysvalaspasnalaleugln
165170175
serglyasnserglngluservalthrgluglnaspserlysaspser
180185190
thrtyrserleuserserthrleuthrleuserlysalaasptyrglu
195200205
lyshislysvaltyralacysgluvalthrhisglnglyleuserser
210215220
provalthrlysserpheasnargglyglucys
225230235
<210>68
<211>465
<212>prt
<213>智人
<400>68
metasptrpthrtrpargileleupheleuvalalaalaalathrgly
151015
alahissergluvalglnleuvalglnserglyalagluvallyslys
202530
proglyserservallysvalsercyslysalaserglyphethrphe
354045
thrasptyrilemethistrpvalargglnalaproglyglnglyleu
505560
glutrpmetglytyrileasnprotyrasnaspaspthrglutyrasn
65707580
glulysphelysglyargvalthrilethralaasplysserthrser
859095
thralatyrmetgluleuserserleuargsergluaspthralaval
100105110
tyrtyrcysalaargseriletyrtyrtyraspalaprophealatyr
115120125
trpglyglnglythrleuvalthrvalserseralaserthrlysgly
130135140
proservalpheproleualaprocysserargserthrsergluser
145150155160
thralaalaleuglycysleuvallysasptyrpheprogluproval
165170175
thrvalsertrpasnserglyalaleuthrserglyvalhisthrphe
180185190
proalavalleuglnserserglyleutyrserleuserservalval
195200205
thrvalproserserasnpheglythrglnthrtyrthrcysasnval
210215220
asphislysproserasnthrlysvalasplysthrvalgluarglys
225230235240
cyscysvalglucysproprocysproalaproprovalalaglypro
245250255
servalpheleupheproprolysprolysaspthrleumetileser
260265270
argthrprogluvalthrcysvalvalvalaspvalserhisgluasp
275280285
progluvalglnpheasntrptyrvalaspglyvalgluvalhisasn
290295300
alalysthrlysproargglugluglnpheasnserthrpheargval
305310315320
valservalleuthrvalvalhisglnasptrpleuasnglylysglu
325330335
tyrlyscyslysvalserasnlysglyleuproalaproileglulys
340345350
thrileserlysthrlysglyglnproarggluproglnvaltyrthr
355360365
leuproproserarggluglumetthrlysasnglnvalserleuthr
370375380
cysleuvallysglyphetyrproseraspilealavalglutrpglu
385390395400
serasnglyglnprogluasnasntyrlysthrthrproprometleu
405410415
aspseraspglyserphepheleutyrserlysleuthrvalasplys
420425430
serargtrpglnglnglyasnvalphesercysservalmethisglu
435440445
alaleuhisasnhistyrthrglnlysserleuserleuserprogly
450455460
lys
465
<210>69
<211>233
<212>prt
<213>智人
<400>69
metglyserthralaileleuglyleuleuleualavalleuglngly
151015
glyargalasertyrvalleuthrglnproproservalservalala
202530
proglyglnthralaargilethrcysglyglyasnasnleuglyser
354045
lysservalhistrptyrglnglnlysproglyglnalaprovalleu
505560
valvaltyraspaspseraspargprosertrpileprogluargphe
65707580
serglyserasnserglyasnthralathrleuthrileserarggly
859095
glualaglyaspglualaasptyrtyrcysglnvaltrpaspserser
100105110
serasphisvalvalpheglyglyglythrlysleuthrvalleugly
115120125
glnprolysalaalaproservalthrleupheproproserserglu
130135140
gluleuglnalaasnlysalathrleuvalcysleuileseraspphe
145150155160
tyrproglyalavalthrvalalatrplysalaaspserserproval
165170175
lysalaglyvalgluthrthrthrproserlysglnserasnasnlys
180185190
tyralaalasersertyrleuserleuthrprogluglntrplysser
195200205
hisargsertyrsercysglnvalthrhisgluglyserthrvalglu
210215220
lysthrvalalaprothrglucysser
225230
<210>70
<211>467
<212>prt
<213>智人
<400>70
metglyserthralaileleuglyleuleuleualavalleuglngly
151015
glyargalaglnmetglnleuvalgluserglyglyglyvalvalgln
202530
proglyargserleuargleusercysalaalaserglyphethrphe
354045
argthrtyrglymethistrpvalargglnalaproglylysglyleu
505560
glutrpvalalavaliletrptyraspglyserasnlyshistyrala
65707580
aspservallysglyargphethrilethrargaspasnserlysasn
859095
thrleuasnleuglnmetasnserleuargalagluaspthralaval
100105110
tyrtyrcysalaargalaproglntrpgluleuvalhisglualaphe
115120125
aspiletrpglyglnglythrmetvalthrvalserseralaserthr
130135140
lysglyproservalpheproleualaprocysserargserthrser
145150155160
gluserthralaalaleuglycysleuvallysasptyrpheproglu
165170175
provalthrvalsertrpasnserglyalaleuthrserglyvalhis
180185190
thrpheproalavalleuglnserserglyleutyrserleuserser
195200205
valvalthrvalproserserasnpheglythrglnthrtyrthrcys
210215220
asnvalasphislysproserasnthrlysvalasplysthrvalglu
225230235240
arglyscyscysvalglucysproprocysproalaproprovalala
245250255
glyproservalpheleupheproprolysprolysaspthrleumet
260265270
ileserargthrprogluvalthrcysvalvalvalaspvalserhis
275280285
gluaspprogluvalglnpheasntrptyrvalaspglyvalgluval
290295300
hisasnalalysthrlysproargglugluglnpheasnserthrphe
305310315320
argvalvalservalleuthrvalvalhisglnasptrpleuasngly
325330335
lysglutyrlyscyslysvalserasnlysglyleuproalaproile
340345350
glulysthrileserlysthrlysglyglnproarggluproglnval
355360365
tyrthrleuproproserarggluglumetthrlysasnglnvalser
370375380
leuthrcysleuvallysglyphetyrproseraspilealavalglu
385390395400
trpgluserasnglyglnprogluasnasntyrlysthrthrpropro
405410415
metleuaspseraspglyserphepheleutyrserlysleuthrval
420425430
asplysserargtrpglnglnglyasnvalphesercysservalmet
435440445
hisglualaleuhisasnhistyrthrglnlysserleuserleuser
450455460
proglylys
465
<210>71
<211>234
<212>prt
<213>智人
<400>71
metglyvalprothrhisleuleuglyleuleuleuleutrpilethr
151015
hisalailecysaspileargmetthrglnserproalaserleuser
202530
alaserleuglygluthrvalasnileglucysleualasergluasp
354045
iletyrseraspleualatrptyrglnglnlysproglylysserpro
505560
glnleuleuiletyrasnalaasnserleuglnasnglyvalproser
65707580
argpheserglyserglyserglythrglntyrserleulysileasn
859095
serleuglnsergluaspvalalathrtyrphecysglnglntyrasn
100105110
asntyrproprothrpheglyglyglythrlysleugluleulysarg
115120125
alaaspalaalaprothrvalserilepheproproserthrglugln
130135140
leualathrglyglyalaservalvalcysleumetasnasnphetyr
145150155160
proargaspileservallystrplysileaspglythrgluargarg
165170175
aspglyvalleuaspservalthraspglnaspserlysaspserthr
180185190
tyrsermetserserthrleuserleuthrlysalaasptyrgluser
195200205
hisasnleutyrthrcysgluvalvalhislysthrserserserpro
210215220
valvallysserpheasnargasnglucys
225230
<210>72
<211>465
<212>prt
<213>智人
<400>72
metaspileargleuserleualapheleuvalleupheilelysgly
151015
valglncysgluvalglnleuvalgluserglyglyglyleuvalgln
202530
proalaasnserleulysleusercysalaalaserglyphethrphe
354045
serasptyralametalatrpvalargglnserprolyslysglyleu
505560
glutrpvalalathrileiletyraspglyserserthrtyrtyrarg
65707580
aspservallysglyargphethrileserargaspasnalalysser
859095
thrleutyrleuglnmetaspserleuargsergluaspthralathr
100105110
tyrtyrcysalathrglyleuglyilealathrasptyrpheasptyr
115120125
trpglyglnglyvalleuvalthrvalserseralagluthrthrala
130135140
proservaltyrproleualaproglythralaleulysserasnser
145150155160
metvalthrleuglycysleuvallysglytyrpheprogluproval
165170175
thrvalthrtrpasnserglyalaleuserserglyvalhisthrphe
180185190
proalavalleuglnserglyleutyrthrleuthrserservalthr
195200205
valproserserthrtrpproserglnthrvalthrcysasnvalala
210215220
hisproalaserserthrlysvalasplyslysilevalproargasn
225230235240
cysglyglyaspcyslysprocysilecysthrglysergluvalser
245250255
servalpheilepheproprolysprolysaspvalleuthrilethr
260265270
leuthrprolysvalthrcysvalvalvalaspileserglnaspasp
275280285
progluvalhisphesertrpphevalaspaspvalgluvalhisthr
290295300
alaglnthrargproproglugluglnpheasnserthrpheargser
305310315320
valsergluleuproileleuhisglnasptrpleuasnglyargthr
325330335
pheargcyslysvalthrseralaalapheproserproileglulys
340345350
thrileserlysprogluglyargthrglnvalprohisvaltyrthr
355360365
metserprothrlysgluglumetthrglnasngluvalserilethr
370375380
cysmetvallysglyphetyrproproaspiletyrvalglutrpgln
385390395400
metasnglyglnproglngluasntyrlysasnthrproprothrmet
405410415
aspthraspglysertyrpheleutyrserlysleuasnvallyslys
420425430
glulystrpglnglnglyasnthrphethrcysservalleuhisglu
435440445
glyleuhisasnhishisthrglulysserleuserhisserprogly
450455460
lys
465
<210>73
<211>237
<212>prt
<213>智人
<400>73
metaspmetargvalproalaglnleuleuglyleuleuleuleutrp
151015
leuargglyalaargcysgluseralaleuthrglnproalaserval
202530
serglyserproglyglnserilethrilesercysthrglythrser
354045
seraspvalglyglytyrasnservalsertrptyrglnglnhispro
505560
glylysalaprolysleumetiletyrgluvalserasnargproser
65707580
glyvalserasnargpheserglyserlysserglyasnthralaser
859095
leuthrileserglyleuglnalagluaspglualaasptyrtyrcys
100105110
asnsertyrthrserthrsermetvalpheglyglyglythrlysleu
115120125
thrvalleuglyglnprolysalaalaproservalthrleuphepro
130135140
proserserglugluleuglnalaasnlysalathrleuvalcysleu
145150155160
ileseraspphetyrproglyalavalthrvalalatrplysalaasp
165170175
serserprovallysalaglyvalgluthrthrthrproserlysgln
180185190
serasnasnlystyralaalasersertyrleuserleuthrproglu
195200205
glntrplysserhisargsertyrsercysglnvalthrhisglugly
210215220
serthrvalglulysthrvalalaprothrglucysser
225230235
<210>74
<211>460
<212>prt
<213>智人
<400>74
metasptrpthrtrpargileleupheleuvalalaalaalathrgly
151015
valhissergluvalglnleuvalglnserglyalagluvallyslys
202530
proglyalaservallysvalsercyslysalaserglytyrthrleu
354045
thrsertyrglyilesertrpvalargglnalaproglyglnglyleu
505560
glutrpmetglytrpvalserphetyrasnglyasnthrasntyrala
65707580
glnlysleuglnglyargglythrmetthrthraspproserthrser
859095
thralatyrmetgluleuargserleuargseraspaspthralaval
100105110
tyrtyrcysalaargglytyrglymetaspvaltrpglyglnglythr
115120125
thrvalthrvalserseralaserthrlysglyproservalphepro
130135140
leualaprocysserargserthrsergluserthralaalaleugly
145150155160
cysleuvallysasptyrpheprogluprovalthrvalsertrpasn
165170175
serglyalaleuthrserglyvalhisthrpheproalavalleugln
180185190
serserglyleutyrserleuserservalvalthrvalproserser
195200205
asnpheglythrglnthrtyrthrcysasnvalasphislysproser
210215220
asnthrlysvalasplysthrvalgluarglyscyscysvalglucys
225230235240
proprocysproalaproprovalalaglyproservalpheleuphe
245250255
proprolysprolysaspthrleumetileserargthrprogluval
260265270
thrcysvalvalvalaspvalserhisgluaspprogluvalglnphe
275280285
asntrptyrvalaspglyvalgluvalhisasnalalysthrlyspro
290295300
argglugluglnpheasnserthrpheargvalvalservalleuthr
305310315320
valvalhisglnasptrpleuasnglylysglutyrlyscyslysval
325330335
serasnlysglyleuproalaproileglulysthrileserlysthr
340345350
lysglyglnproarggluproglnvaltyrthrleuproproserarg
355360365
gluglumetthrlysasnglnvalserleuthrcysleuvallysgly
370375380
phetyrproseraspilealavalglutrpgluserasnglyglnpro
385390395400
gluasnasntyrlysthrthrproprometleuaspseraspglyser
405410415
phepheleutyrserlysleuthrvalasplysserargtrpglngln
420425430
glyasnvalphesercysservalmethisglualaleuhisasnhis
435440445
tyrthrglnlysserleuserleuserproglylys
450455460
<210>75
<211>234
<212>prt
<213>智人
<400>75
metgluthrproalaglnleuleupheleuleuleuleutrpleupro
151015
aspthrthrglygluilevalmetthrglnserproalathrleuser
202530
valserproglygluargalathrleusercysargalaserglnser
354045
valserserasnleualatrptyrglnglnlysproglyglnalapro
505560
argleuleuiletyrglyalaalathrargalathrglyileproala
65707580
argvalserglyserglyserglythrgluphethrleuthrileser
859095
serleuglnsergluaspphealavaltyrtyrcysglnglntyrasn
100105110
asntrpproleuthrpheglyglyglythrlysvalgluilelysarg
115120125
thrvalalaalaproservalpheilepheproproseraspglugln
130135140
leulysserglythralaservalvalcysleuleuasnasnphetyr
145150155160
proargglualalysvalglntrplysvalaspasnalaleuglnser
165170175
glyasnserglngluservalthrgluglnaspserlysaspserthr
180185190
tyrserleuserserthrleuthrleuserlysalaasptyrglulys
195200205
hislysvaltyralacysgluvalthrhisglnglyleuserserpro
210215220
valthrlysserpheasnargglyglucys
225230
<210>76
<211>472
<212>prt
<213>智人
<400>76
metaspmetargvalproalaglnleuleuglyleuleuleuleutrp
151015
leuargglyalaargcysglnvalglnleuvalgluserglyglygly
202530
valvalglnproglyargserleuargleusercysalaalasergly
354045
phethrpheserasntyrglymethistrpvalargglnalaprogly
505560
gluglyleuglutrpvalalaalailetrppheaspalaserasplys
65707580
tyrtyralaaspalavallysglyargphethrileserargaspasn
859095
serlysasnthrleutyrleuglnmetasnserleuargalagluasp
100105110
thralavaltyrtyrcysalaargaspglnalailepheglyvalval
115120125
proasptyrtrpglyglnglythrleuvalthrvalserseralaser
130135140
thrlysglyproservalpheproleualaproserserlysserthr
145150155160
serglyglythralaalaleuglycysleuvallysasptyrphepro
165170175
gluprovalthrvalsertrpasnserglyalaleuthrserglyval
180185190
histhrpheproalavalleuglnserserglyleutyrserleuser
195200205
servalvalthrvalproserserserleuglythrglnthrtyrile
210215220
cysasnvalasnhislysproserasnthrlysvalasplyslysval
225230235240
gluprolyssercysasplysthrhisthrcysproprocysproala
245250255
progluleuleuglyglyproservalpheleupheproprolyspro
260265270
lysaspthrleumetileserargthrprogluvalthrcysvalval
275280285
valaspvalserhisgluaspprogluvallyspheasntrptyrval
290295300
aspglyvalgluvalhisasnalalysthrlysprocysgluglugln
305310315320
tyrglyserthrtyrargcysvalservalleuthrvalleuhisgln
325330335
asptrpleuasnglylysglutyrlyscyslysvalserasnlysala
340345350
leuproalaproileglulysthrileserlysalalysglyglnpro
355360365
arggluproglnvaltyrthrleuproproserarggluglumetthr
370375380
lysasnglnvalserleuthrcysleuvallysglyphetyrproser
385390395400
aspilealavalglutrpgluserasnglyglnprogluasnasntyr
405410415
lysthrthrproprovalleuaspseraspglyserphepheleutyr
420425430
serlysleuthrvalasplysserargtrpglnglnglyasnvalphe
435440445
sercysservalmethisglualaleuhisasnhistyrthrglnlys
450455460
serleuserleuserproglylys
465470
<210>77
<211>231
<212>prt
<213>智人
<400>77
metalatrpileproleupheleuglyvalleualatyrcysthrgly
151015
servalalasertyrgluvalthrglnalaproservalservalser
202530
proglyglnthralaserilethrcysserglyasplysleuglyasp
354045
lystyralacystrptyrglnglnlysproglyglnserprovalleu
505560
valiletyrglnaspserlysargproserglyileprogluargphe
65707580
serglyserasnserglyasnthralathrleuthrileserglythr
859095
glnalametaspglualaasptyrtyrcysglnalatrpaspserser
100105110
thralavalpheglyglyglythrlysleuthrvalleuglyglnpro
115120125
lysalaalaproservalthrleupheproproserserglugluleu
130135140
glnalaasnlysalathrleuvalcysleuileseraspphetyrpro
145150155160
glyalavalthrvalalatrplysalaaspserserprovallysala
165170175
glyvalgluthrthrthrproserlysglnserasnasnlystyrala
180185190
alasersertyrleuserleuthrprogluglntrplysserhisarg
195200205
sertyrsercysglnvalthrhisgluglyserthrvalglulysthr
210215220
valalaprothrglucysser
225230
<210>78
<211>467
<212>prt
<213>智人
<400>78
metasptrpthrtrpserileleupheleuvalalaalaalathrgly
151015
alahisserglnvalglnleuvalglnserglyalagluvallyslys
202530
proglyalaservallysvalsercyslysalaserglytyrthrphe
354045
thrsertyrglyleusertrpvalargglnalaproglyglnglyleu
505560
glutrpmetglytrpileileprotyrasnglyasnthrasnserala
65707580
glnlysleuglnglyargvalthrmetthrthraspthrserthrser
859095
thralatyrmetgluleuargserleuargseraspaspthralaval
100105110
tyrphecysalaargaspargasptyrglyvalasntyraspalaphe
115120125
aspiletrpglyglnglythrmetvalthrvalserseralaserthr
130135140
lysglyproservalpheproleualaprocysserargserthrser
145150155160
gluserthralaalaleuglycysleuvallysasptyrpheproglu
165170175
provalthrvalsertrpasnserglyalaleuthrserglyvalhis
180185190
thrpheproalavalleuglnserserglyleutyrserleuserser
195200205
valvalthrvalproserserasnpheglythrglnthrtyrthrcys
210215220
asnvalasphislysproserasnthrlysvalasplysthrvalglu
225230235240
arglyscyscysvalglucysproprocysproalaproprovalala
245250255
glyproservalpheleupheproprolysprolysaspthrleumet
260265270
ileserargthrprogluvalthrcysvalvalvalaspvalserhis
275280285
gluaspprogluvalglnpheasntrptyrvalaspglyvalgluval
290295300
hisasnalalysthrlysproargglugluglnpheasnserthrphe
305310315320
argvalvalservalleuthrvalvalhisglnasptrpleuasngly
325330335
lysglutyrlyscyslysvalserasnlysglyleuproalaproile
340345350
glulysthrileserlysthrlysglyglnproarggluproglnval
355360365
tyrthrleuproproserarggluglumetthrlysasnglnvalser
370375380
leuthrcysleuvallysglyphetyrproseraspilealavalglu
385390395400
trpgluserasnglyglnprogluasnasntyrlysthrthrpropro
405410415
metleuaspseraspglyserphepheleutyrserlysleuthrval
420425430
asplysserargtrpglnglnglyasnvalphesercysservalmet
435440445
hisglualaleuhisasnhistyrthrglnlysserleuserleuser
450455460
proglylys
465
<210>79
<211>235
<212>prt
<213>智人
<400>79
metalatrpalaproleuleuleuthrleuleualahiscysthrgly
151015
sertrpalaasnphemetleuthrglnprohisservalsergluser
202530
proglylysthrvalalailesercysthrargasnserglyserile
354045
alaserasnservalglntrptyrglnglnargproglyserserpro
505560
thrthrvalilephegluaspasnglnargproserglyvalproasp
65707580
argpheserglyserileaspserserserasnseralaserleuthr
859095
ileserglyleulysthrgluaspglualaasptyrtyrcysglnser
100105110
tyraspserasnasntrpvalpheglyglyglythrlysleuthrval
115120125
leuglyglnprolysalaasnprothrvalthrleupheproproser
130135140
serglugluleuglnalaasnlysalathrleuvalcysleuileser
145150155160
aspphetyrproglyalavalthrvalalatrplysalaaspglyser
165170175
provallysalaglyvalgluthrthrlysproserlysglnserasn
180185190
asnlystyralaalasersertyrleuserleuthrprogluglntrp
195200205
lysserhisargsertyrsercysglnvalthrhisgluglyserthr
210215220
valglulysthrvalalaprothrglucysser
225230235
<210>80
<211>470
<212>prt
<213>智人
<400>80
metglupheglyleusertrpvalpheleuvalalaleuleuarggly
151015
valglncysglnvalglnleuvalgluserglyglyglyvalvalgln
202530
proglyargserleuargleusercysalaalaserglyphethrphe
354045
sersertyrvalmethistrpvalargglnalaproglylysglyleu
505560
glutrpvalalavaliletrptyraspglyserasnlystyrtyrala
65707580
aspservallysglyargphethrileserargaspasnserlysasn
859095
thrleutyrleuglnmetasnserleuargalagluaspthralaval
100105110
tyrtyrcysalaarggluglytyrasptyrglygluasptyrtyrtyr
115120125
tyrglymetaspvaltrpglyglnglythrthrvalthrvalserser
130135140
alaserthrlysglyproservalpheproleualaprocysserarg
145150155160
serthrsergluserthralaalaleuglycysleuvallysasptyr
165170175
pheprogluprovalthrvalsertrpasnserglyalaleuthrser
180185190
glyvalhisthrpheproalavalleuglnserserglyleutyrser
195200205
leuserservalvalthrvalproserserasnpheglythrglnthr
210215220
tyrthrcysasnvalasphislysproserasnthrlysvalasplys
225230235240
thrvalgluarglyscyscysvalglucysproprocysproalapro
245250255
provalalaglyproservalpheleupheproprolysprolysasp
260265270
thrleumetileserargthrprogluvalthrcysvalvalvalasp
275280285
valserhisgluaspprogluvalglnpheasntrptyrvalaspgly
290295300
valgluvalhisasnalalysthrlysproargglugluglnpheasn
305310315320
serthrpheargvalvalservalleuthrvalvalhisglnasptrp
325330335
leuasnglylysglutyrlyscyslysvalserasnlysglyleupro
340345350
alaproileglulysthrileserlysthrlysglyglnproargglu
355360365
proglnvaltyrthrleuproproserarggluglumetthrlysasn
370375380
glnvalserleuthrcysleuvallysglyphetyrproseraspile
385390395400
alavalglutrpgluserasnglyglnprogluasnasntyrlysthr
405410415
thrproprometleuaspseraspglyserphepheleutyrserlys
420425430
leuthrvalasplysserargtrpglnglnglyasnvalphesercys
435440445
servalmethisglualaleuhisasnhistyrthrglnlysserleu
450455460
serleuserproglylys
465470
<210>81
<211>236
<212>prt
<213>智人
<400>81
metaspmetargvalproalaglnleuleuglyleuleuleuleutrp
151015
leuargglyalaargcysaspileglnmetthrglnserproserser
202530
leuseralaservalglyaspargvalthrilethrcysargalaser
354045
glnaspileserasntyrleuasntrptyrglnglnlysproglylys
505560
alaprolysleuleuiletyrtyrthrserargleuleuserglyval
65707580
proserargpheserglyserglyserglythraspphethrleuthr
859095
ileserserleuglnprogluaspphealathrtyrtyrcysglngln
100105110
glyaspthrleuprotyrthrpheglyglyglythrlysvalgluile
115120125
lysargthrvalalaalaproservalpheilepheproproserasp
130135140
gluglnleulysserglythralaservalvalcysleuleuasnasn
145150155160
phetyrproargglualalysvalglntrplysvalaspasnalaleu
165170175
glnserglyasnserglngluservalthrgluglnaspserlysasp
180185190
serthrtyrserleuserserthrleuthrleuserlysalaasptyr
195200205
glulyshislysvaltyralacysgluvalthrhisglnglyleuser
210215220
serprovalthrlysserpheasnargglyglucys
225230235
<210>82
<211>468
<212>prt
<213>智人
<400>82
metasptrpthrtrpargileleupheleuvalalaalaalathrgly
151015
alahissergluvalglnleuvalglnserglyalagluvallyslys
202530
proglyalaservallysvalsercyslysalaserglytyrthrphe
354045
thrasptyrasnmethistrpvalargglnalaproglyglnglyleu
505560
glutrpmetglygluileasnproasnserglyglyalaglytyrasn
65707580
glnlysphelysglyargvalthrmetthrthraspthrserthrser
859095
thralatyrmetgluleuargserleuargseraspaspthralaval
100105110
tyrtyrcysalaargleuglytyraspaspiletyraspasptrptyr
115120125
pheaspvaltrpglyglnglythrthrvalthrvalserseralaser
130135140
thrlysglyproservalpheproleualaprocysserargserthr
145150155160
sergluserthralaalaleuglycysleuvallysasptyrphepro
165170175
gluprovalthrvalsertrpasnserglyalaleuthrserglyval
180185190
histhrpheproalavalleuglnserserglyleutyrserleuser
195200205
servalvalthrvalproserserasnpheglythrglnthrtyrthr
210215220
cysasnvalasphislysproserasnthrlysvalasplysthrval
225230235240
gluarglyscyscysvalglucysproprocysproalaproproval
245250255
alaglyproservalpheleupheproprolysprolysaspthrleu
260265270
metileserargthrprogluvalthrcysvalvalvalaspvalser
275280285
hisgluaspprogluvalglnpheasntrptyrvalaspglyvalglu
290295300
valhisasnalalysthrlysproargglugluglnpheasnserthr
305310315320
pheargvalvalservalleuthrvalvalhisglnasptrpleuasn
325330335
glylysglutyrlyscyslysvalserasnlysglyleuproalapro
340345350
ileglulysthrileserlysthrlysglyglnproarggluprogln
355360365
valtyrthrleuproproserarggluglumetthrlysasnglnval
370375380
serleuthrcysleuvallysglyphetyrproseraspilealaval
385390395400
glutrpgluserasnglyglnprogluasnasntyrlysthrthrpro
405410415
prometleuaspseraspglyserphepheleutyrserlysleuthr
420425430
valasplysserargtrpglnglnglyasnvalphesercysserval
435440445
methisglualaleuhisasnhistyrthrglnlysserleuserleu
450455460
serproglylys
465
<210>83
<211>240
<212>prt
<213>智人
<400>83
metvalleuglnthrglnvalpheileserleuleuleutrpileser
151015
glyalatyrglyaspilevalmetthrglnserproaspserleuala
202530
valserleuglygluargalathrileasncyslysserserglnser
354045
valleuaspserseraspasnlysasntyrleualatrptyrglngln
505560
lysproglyglnproprolysleuleuiletyrtrpalaserasnarg
65707580
gluserglyvalproaspargpheserglyserglyserglythrasp
859095
phethrleuthrileserserleuglnalagluaspvalalavaltyr
100105110
tyrcysglnglntyrtyrseraspprophethrpheglyproglythr
115120125
lysvalaspilelysargthrvalalaalaproservalpheilephe
130135140
proproseraspgluglnleulysserglythralaservalvalcys
145150155160
leuleuasnasnphetyrproargglualalysvalglntrplysval
165170175
aspasnalaleuglnserglyasnserglngluservalthrglugln
180185190
aspserlysaspserthrtyrserleuserserthrleuthrleuser
195200205
lysalaasptyrglulyshislysvaltyralacysgluvalthrhis
210215220
glnglyleuserserprovalthrlysserpheasnargglyglucys
225230235240
<210>84
<211>465
<212>prt
<213>智人
<400>84
metasptrpthrtrpserileleupheleuvalalaalaprothrgly
151015
alahisserglnvalglnleuvalglnserglyalagluvallyslys
202530
proglyalaservallysvalsercyslysalaserglytyrthrphe
354045
thrsertyrglyilesertrpvalargglnalaproglyglnglyleu
505560
glutrpmetglytrpileseralatyrasnglyasnthrasntyrala
65707580
glnlysleuglnglyargvalthrmetthrthraspthrserthrser
859095
thralatyrmetgluleuargserleuargseraspaspthralaval
100105110
tyrtyrcysalaargglusertrppheglygluvalphepheasptyr
115120125
trpglyglnglythrleuvalthrvalserseralaserthrlysgly
130135140
proservalpheproleualaprocysserargserthrsergluser
145150155160
thralaalaleuglycysleuvallysasptyrpheprogluproval
165170175
thrvalsertrpasnserglyalaleuthrserglyvalhisthrphe
180185190
proalavalleuglnserserglyleutyrserleuserservalval
195200205
thrvalproserserasnpheglythrglnthrtyrthrcysasnval
210215220
asphislysproserasnthrlysvalasplysthrvalgluarglys
225230235240
cyscysvalglucysproprocysproalaproprovalalaglypro
245250255
servalpheleupheproprolysprolysaspthrleumetileser
260265270
argthrprogluvalthrcysvalvalvalaspvalserhisgluasp
275280285
progluvalglnpheasntrptyrvalaspglyvalgluvalhisasn
290295300
alalysthrlysproargglugluglnpheasnserthrpheargval
305310315320
valservalleuthrvalvalhisglnasptrpleuasnglylysglu
325330335
tyrlyscyslysvalserasnlysglyleuproalaproileglulys
340345350
thrileserlysthrlysglyglnproarggluproglnvaltyrthr
355360365
leuproproserarggluglumetthrlysasnglnvalserleuthr
370375380
cysleuvallysglyphetyrproseraspilealavalglutrpglu
385390395400
serasnglyglnprogluasnasntyrlysthrthrproprometleu
405410415
aspseraspglyserphepheleutyrserlysleuthrvalasplys
420425430
serargtrpglnglnglyasnvalphesercysservalmethisglu
435440445
alaleuhisasnhistyrthrglnlysserleuserleuserprogly
450455460
lys
465
<210>85
<211>236
<212>prt
<213>智人
<400>85
metaspmetargvalproalaglnleuleuglyleuleuleuleutrp
151015
leuargglyalaargcysaspileglnmetthrglnserproserser
202530
valseralaservalglyaspargvalthrilethrcysargalaser
354045
glnglyilesersertrpleualatrptyrglnglnlysproglylys
505560
alaprolysleuleuiletyrglyalaserasnleugluserglyval
65707580
proserargpheserglyserglyserglythraspphethrleuthr
859095
ileserserleuglnprogluaspphealaasntyrtyrcysglngln
100105110
alaasnserpheprotrpthrpheglyglnglythrlysvalgluile
115120125
lysargthrvalalaalaproservalpheilepheproproserasp
130135140
gluglnleulysserglythralaservalvalcysleuleuasnasn
145150155160
phetyrproargglualalysvalglntrplysvalaspasnalaleu
165170175
glnserglyasnserglngluservalthrgluglnaspserlysasp
180185190
serthrtyrserleuserserthrleuthrleuserlysalaasptyr
195200205
glulyshislysvaltyralacysgluvalthrhisglnglyleuser
210215220
serprovalthrlysserpheasnargglyglucys
225230235
<210>86
<211>466
<212>prt
<213>智人
<400>86
metaspmetargvalproalaglnleuleuglyleuleuleuleutrp
151015
leuargglyalaargcysglnvalglnleuvalglnserglyalaglu
202530
vallyslysproglyalaservallysvalsercyslysvalsergly
354045
tyrthrleuseraspleuserilehistrpvalargglnalaprogly
505560
lysglyleuglutrpmetglyglypheaspproglnaspglygluthr
65707580
iletyralaglnlyspheglnglyargvalthrmetthrgluaspthr
859095
serthraspthralatyrmetgluleuserserleulyssergluasp
100105110
thralavaltyrtyrcysalathrglysersersersertrppheasp
115120125
protrpglyglnglythrleuvalthrvalserseralaserthrlys
130135140
glyproservalpheproleualaprocysserargserthrserglu
145150155160
serthralaalaleuglycysleuvallysasptyrpheproglupro
165170175
valthrvalsertrpasnserglyalaleuthrserglyvalhisthr
180185190
pheproalavalleuglnserserglyleutyrserleuserserval
195200205
valthrvalproserserasnpheglythrglnthrtyrthrcysasn
210215220
valasphislysproserasnthrlysvalasplysthrvalgluarg
225230235240
lyscyscysvalglucysproprocysproalaproprovalalagly
245250255
proservalpheleupheproprolysprolysaspthrleumetile
260265270
serargthrprogluvalthrcysvalvalvalaspvalserhisglu
275280285
aspprogluvalglnpheasntrptyrvalaspglyvalgluvalhis
290295300
asnalalysthrlysproargglugluglnpheasnserthrphearg
305310315320
valvalservalleuthrvalvalhisglnasptrpleuasnglylys
325330335
glutyrlyscyslysvalserasnlysglyleuproalaproileglu
340345350
lysthrileserlysthrlysglyglnproarggluproglnvaltyr
355360365
thrleuproproserarggluglumetthrlysasnglnvalserleu
370375380
thrcysleuvallysglyphetyrproseraspilealavalglutrp
385390395400
gluserasnglyglnprogluasnasntyrlysthrthrpropromet
405410415
leuaspseraspglyserphepheleutyrserlysleuthrvalasp
420425430
lysserargtrpglnglnglyasnvalphesercysservalmethis
435440445
glualaleuhisasnhistyrthrglnlysserleuserleuserpro
450455460
glylys
465