CN1993379A

CN1993379A - 抗il－13抗体、抗il－13抗体的晶体以及包含它们的复合物

Info

Publication number: CN1993379A
Application number: CNA2005800268419A
Authority: CN
Inventors: L·L·林; K·D·帕里斯; A·S·P·塔姆; X-Y·谭; T·沙内; J·杜马斯; J·M·威廉; M·施塔尔; L·莫夏科; Z·胡
Original assignee: Wyeth LLC
Current assignee: Wyeth LLC
Priority date: 2004-06-09
Filing date: 2005-06-09
Publication date: 2007-07-04

Abstract

本发明公开了抗白介素13(IL－13)抗体、抗IL－13抗体晶体、IL－13多肽/抗IL－13抗体复合物、IL－13多肽/抗IL－13抗体复合物的晶体、IL－13Rα1多肽/IL－13多肽/抗IL－13抗体复合物、IL－13Rα1多肽/IL－13多肽/抗IL－13抗体复合物的晶体，以及相关方法和软件系统。

Description

抗IL-13抗体、抗IL-13抗体的晶体以及包含它们的复合物

相关申请

本申请要求于2004年6月9日递交的美国临时专利申请号60/578,736、于2004年6月9日递交的美国临时专利申请号60/578,473，以及于2004年6月22日递交的美国临时专利申请号60/581,375的权益。其每一申请内容均在此处完整引用作为参考。

技术领域

本发明涉及抗IL-13抗体、抗IL-13抗体晶体、IL-13多肽/抗IL-13抗体复合物、IL-13多肽/抗IL-13抗体复合物的晶体、IL-13Rα1多肽/IL-13多肽/抗IL-13抗体复合物、IL-13Rα1多肽/IL-13多肽/抗IL-13抗体复合物的晶体，以及相关方法和软件系统。

发明背景

白介素13(IL-13)为诸如特应性、哮喘、过敏和炎症性反应等免疫应答疾病涉及的多效性细胞因子。IL-13在免疫应答中的作用受其在细胞信号转导中的效应促进。例如，IL-13能够促进B细胞增殖、诱导B细胞产生IgE，并下调促炎症性细胞因子的产生。IL-13也能增强VCAM-1在内皮细胞中的表达，增强II类MHC抗原以及多种粘附分子在单核细胞中的表达。

IL-13与造血细胞及其他类型细胞上其受体间的相互作用介导其功能。人IL-13受体(IL-13R)为包括白介素4受体α链IL-4Rα及IL-13结合链IL-13Rα1的异二聚体。通过与IL-4Rα链的结合相互作用，IL-13与其受体的结合引发STAT6(信号转导和转录激活因子6)和JAK1(Janus家族激酶)的活化。IL-13Rα2可见于细胞表面或为循环中的可溶形式，以高亲和力结合于IL-13但并不介导对IL-13的细胞应答。认为其作为假受体起作用。

发明概述

本发明的一个方面描述了晶体抗体。该晶体抗体为抗IL-13抗体或抗IL-13抗体的Fab片段。

本发明的另一方面描述了包括抗体的晶体组合物。所述抗体为抗IL-13抗体或抗IL-13抗体的Fab片段。

本发明的另一方面描述了包括IL-13多肽和抗体的晶体复合物。所述抗体为抗IL-13抗体或抗IL-13抗体的Fab片段。

本发明的另一方面描述了包括IL-13Rα1多肽和IL-13多肽的晶体复合物。

本发明的又一方面描述了包括利用抗体的三维模型设计与IL-13多肽相互作用的物质的方法。所述抗体为抗IL-13抗体或抗IL-13抗体的Fab片段。

本发明的另一方面描述了包括利用IL-13多肽的三维模型设计与IL-13多肽相互作用的物质的方法。

本发明的另一方面描述了包括利用结合于IL-13Rα1多肽的IL-13多肽的三维模型设计与IL-13多肽相互作用的物质的方法。

本发明的另一方面描述了这样的方法，所述方法包括利用包含IL-13多肽的晶体复合物的三维结构进行合理的药物设计来选择物质；将所述物质与IL-13多肽接触；并检测所述物质结合IL-13多肽的能力。

本发明的另一方面描述了这样的方法，所述方法包括将IL-13多肽与抗体接触以形成组合物；使所述组合物晶体化以形成晶体复合物，其中抗体结合于IL-13多肽。所述抗体为抗IL-13抗体或抗IL-13抗体的Fab片段，且所述晶体复合物能衍射X射线，分辨率至少约3.5_。

本发明的另一方面描述了这样的方法，所述方法包括将IL-13多肽与抗体和IL-13Rα1多肽接触以形成组合物；使所述组合物晶体化以形成晶体复合物，其中抗体和IL-13Rα1多肽各自结合于IL-13多肽。所述抗体为抗IL-13抗体或抗IL-13抗体的Fab片段，且所述晶体复合物能衍射X射线，分辨率至少约3.5_。

本发明的另一方面描述了这样的软件系统，其中包括令计算机系统接受有关结合于抗体的IL-13多肽结构信息的指令，所述抗体包括抗IL-13抗体或抗IL-13抗体的Fab片段。这些指令也令计算机系统接受有关候选物质的信息，并确定所述候选物质与IL-13多肽的结合特性。结合特性的确定是基于有关IL-13多肽结构的信息以及有关候选物质的信息。

本发明的另一方面描述了存储于计算机可读介质中的计算机程序。计算机可读介质中存储了大量指令。当一个或多个处理器执行这些指令时，所述一个或多个处理器将接受有关结合于抗体的IL-13多肽结构的信息，所述抗体为抗IL-13抗体或抗IL-13抗体的Fab片段；还将接受有关候选物质的信息；并确定所述候选物质与IL-13多肽的结合特性。结合特性的确定是基于有关IL-13多肽结构的信息以及有关候选物质的信息。

本发明的另一方面描述了包括接受有关结合于抗体的IL-13多肽结构的信息，并构建IL-13多肽与候选物质的结合特性模型的方法。所述抗体为抗IL-13抗体或抗IL-13抗体的Fab片段。接受信息和建模结合特性的方法由软件系统执行。

本发明的另一方面描述了存储于计算机可读介质的包含大量指令的计算机程序。当一个或多个处理器执行这些指令时，所述一个或多个处理器将接受有关结合于抗体的IL-13多肽结构的信息，所述抗体为抗IL-13抗体或抗IL-13抗体的Fab片段；并构建IL-13多肽与候选物质结合特性模型。

本发明的另一方面描述了这样的软件系统，其中包括指令使计算机系统接受有关结合于抗体的IL-13多肽结构的信息，并构建IL-13多肽与候选物质的结合特性模型。所述抗体为抗IL-13抗体或抗IL-13抗体的Fab片段。

本发明的另一方面描述了晶体抗体。所述抗体能够结合IL-4R多肽与之体内结合的IL-13多肽上的位点。

本发明的另一方面描述了包括这样的抗体的晶体组合物，所述抗体能够结合IL-4R多肽与之体内结合的IL-13多肽上的位点。

本发明的另一方面描述了包括IL-13多肽及抗体的晶体复合物。所述抗体能够结合IL-4R多肽与之体内结合的IL-13多肽上的位点。

本发明的另一方面描述了包括IL-13多肽、IL-13Rα1多肽及抗体的晶体复合物。所述抗体能够结合IL-4R多肽与之体内结合的IL-13多肽上的位点。

本发明的另一方面描述了包括利用抗体的三维模型设计与IL-13多肽相互作用的物质的方法。所述抗体能够结合IL-4R多肽与之体内结合的IL-13多肽上的位点。

本发明的另一方面描述了这样的方法，所述方法包括将IL-13多肽与抗体接触以形成组合物；使所述组合物晶体化以形成晶体复合物，其中抗体结合于IL-13多肽。所述抗体能够结合IL-4R多肽与之体内结合的IL-13多肽上的位点，且所述晶体复合物能衍射X射线，分辨率至少约3.5_。

本发明的又一方面描述了这样的方法，包括将IL-13多肽与抗体和IL-13Rα1多肽接触以形成组合物；使所述组合物晶体化以形成晶体复合物，其中抗体和IL-13Rα1多肽各自结合于IL-13多肽。所述抗体能够结合IL-4R多肽与之体内结合的IL-13多肽上的位点，且所述晶体复合物能衍射X射线，分辨率至少约3.5_。

本发明的另一方面描述了这样的软件系统，其中包括令计算机系统接受有关结合于抗体的IL-13多肽结构的信息、接受有关候选物质的信息的指令，并确定该候选物质与IL-13多肽的结合特性。所述抗体能够结合IL-4R多肽与之体内结合的IL-13多肽上的位点。所述候选物质结合特性的确定基于有关IL-13多肽结构的信息以及有关候选物质的信息。

本发明的另一方面描述了存储于计算机可读介质的包括大量指令的计算机程序。当一个或多个处理器执行这些指令时，所述一个或多个处理器将接受有关结合于抗体的IL-13多肽结构的信息、接受有关候选物质的信息；并确定所述候选物质与IL-13多肽的结合特性。所述抗体能够结合IL-4R多肽与之体内结合的IL-13多肽上的位点。候选物质结合特性的确定基于有关IL-13多肽结构的信息以及有关候选物质的信息。

本发明的另一方面描述了包括接受有关结合于抗体的IL-13多肽结构的信息，并构建IL-13多肽与候选物质的结合特性模型的方法。所述抗体能够结合IL-4R多肽与之体内结合的IL-13多肽上的位点。接受信息和建模结合特性的方法由软件系统执行。

本发明的另一方面描述了存储于计算机可读介质的包括大量指令的计算机程序。当一个或多个处理器执行这些指令时，所述一个或多个处理器将接受有关结合于抗体的IL-13多肽结构的信息，并构建IL-13多肽与候选物质的结合特性模型。所述抗体能够结合IL-4R多肽与之体内结合的IL-13多肽上的位点。

本发明的另一方面描述了这样的软件系统，其中包括指令使计算机系统接受有关结合于抗体的IL-13多肽结构的信息，并构建IL-13多肽与候选物质的结合特性模型。所述抗体能够结合IL-13多肽上体内由IL-4R多肽结合的位点。

本发明的另一方面描述了调节受试者中IL-13活性的方法。所述方法包括利用合理的药物设计选择能调节IL-13活性的物质，并对受试者施用治疗有效量的所述物质。

本发明的另一方面描述了治疗患有IL-13活性相关疾病的受试者的方法。所述方法包括利用合理药物设计选择能影响IL-13活性的物质，并对受试者施用治疗有效量的所述物质。

本发明的另一方面描述了预防性治疗对IL-13活性相关疾病易感受试者的方法。包括确定对IL-13活性相关疾病易感的受试者，利用合理药物设计选择能影响IL-13活性的物质，并对受试者施用治疗有效量的所述物质。

多肽或其相应配体的结构信息有助于更好理解多肽在体内是如何行使功能的。例如，有关蛋白质或其相应配体的知识能提示有助于蛋白质与其配体相互作用的性质，所述配体包括其他蛋白质、抗体、效应分子(如激素)以及核酸。基于结构的建模可用于鉴定能与IL-13多肽相互作用的配体，从而不需要进行昂贵和费时的筛查测定。结构信息也可用于指导修饰已知与IL-13多肽相互作用的配体，产生具有更多期望性质(如结合更紧密或特异性更强)的替代配体。

有关抗IL-13抗体与IL-13多肽以及IL-13多肽与其受体间相互作用的研究，有助于设计或选择配体(如药物)调节IL-13的体内活性。因此，此类研究有助于设计治疗剂。活性测定提示mAb13.2阻断了IL-13的体外和体内功能(见下文实施例1和2)，包括利用抗体鉴定能干扰该蛋白质正常功能的IL-13结合物质。因此，mAb13.2 Fab片段、人IL-13/mAb13.2 Fab片段复合物以及人IL-13Rα1多肽/人IL-13/mAb13.2 Fab片段复合物(见下表10-12)的晶体结构，可用于设计或鉴定能与IL-13以及IL-13受体多肽IL-13Rα1相互作用的物质。此类物质可用于调节免疫反应性疾病中IL-13的活性，例如哮喘(如非过敏性哮喘或过敏性哮喘，后者有时被称作慢性过敏性气道疾病)、慢性阻塞性肺病(COPD)、气道炎症、嗜酸性粒细胞增多症、纤维化及过量粘液产生(如囊性纤维化、肺纤维化和过敏性鼻炎)、皮肤炎症性和/或自身免疫性疾病(如特应性皮炎)、胃肠道器官炎症性和/或自身免疫性疾病(如炎症性肠病(IBD)和/或Crohn’s病)、肝脏(如肝硬化)、血管或结缔组织炎症性和/或自身免疫性疾病(如硬皮病)，以及肿瘤或癌症(如软组织或实体肿瘤)如霍奇金淋巴瘤、胶质母细胞瘤和淋巴瘤。

从所附附图和描述以及权利要求中，本发明的其他特征和优势将会变得显而易见。本申请中引用的所有参考文献的内容、未决专利申请以及出版专利，均在此处明确引用作为参考。如有矛盾，以本申请(包括定义)为准。

附图简述

图1A为mAb13.2 Fab(抗原结合片段)片段轻链的氨基酸序列(SEQID NO：1)。

图1B为mAb13.2 Fab片段重链的氨基酸序列(SEQ ID NO：2)。

图2A为全长人IL-13的氨基酸序列(Swiss-Prot登录号P35225)(SEQID NO：3)。信号肽裂解位点以“/”表示。α螺旋A、B、C和D以下划线表示。螺旋A定义为25-42位氨基酸；螺旋B定义为62-71位氨基酸；螺旋C定义为78-89位氨基酸；螺旋D定义为112-127位氨基酸。

图2B为信号肽裂解后的人IL-13的氨基酸序列(SEQ ID NO：4)。α螺旋A、B、C和D以下划线表示。螺旋A定义为6-23位氨基酸；螺旋B定义为43-52位氨基酸；螺旋C定义为59-70位氨基酸；螺旋D定义为93-108位氨基酸。

图3为图示了mAb13.2 Fab片段(左侧)以及加工后形式人IL-13(见图2B)(右侧)的晶体结构的带状图。mAb13.2 Fab片段的轻链显示为深色阴影，而重链为浅色阴影。IL-13结构中的螺旋A、B、C和D如图所示。

图4图示了Biacore分析中，结合人IL-13的3种不同抗IL-13抗体(mAb13.2、mAb13.4和mAb13.9)的动力学参数。也显示了mAb13.2的动力学常量。

图5为图示生物素化mAb13.2与重组及天然人IL-13结合的图表。用抗FLAG M2抗体包被ELISA板。利用生物素化mAb13.2和链酶亲和素-过氧化氢酶检测FLAG-人IL-13的结合。分离自丝裂原活化、Th2偏移的脐带血单核细胞的天然人IL-13(三角形)以及重组人IL-13(菱形)能竞争这一结合。未检测到重组鼠IL-13(圆圈)与mAb13.2的结合。

图6为图示了mAb13.2及已知抑制剂rhuIL-13Rα2对人IL-13生物活性的影响的图表。“cpm”为TF1细胞摄取³H-胸苷的度量单位，所述细胞在IL-13及不同浓度mAb13.2或rhuIL-13Rα2(x轴)存在下培养。

图7A为图示了重组人IL-13和IL-14对CD11b⁺单核细胞上的CD23表达的影响的图表。所述单核细胞为收集自健康供体的正常外周血单核细胞(PBMC)。用1ng/ml重组人IL-13或IL-14处理这些细胞过夜，然后用流式细胞仪测定CD23的表达。

图7B为图示了mAb13.2对于CD11b⁺单核细胞上IL-13诱导的CD23表达的影响的图表。

图7C为图示了mAb13.2对于CD11b⁺单核细胞上IL-4诱导的CD23表达的影响的图表。

图8为图示了mAb13.2对人B细胞中IL-13依赖性的IgE产生的影响的图表。用PHA和IL-13刺激来自健康供体的PBMC。3周后，用ELISA测定每孔中的IgE浓度。PHA+IL-13增加了产IgE的B细胞克隆的频率。这一效应被mAb13.2所抑制，但不被IL-13特异性非中和抗体(mAb13.8)或对照小鼠IgG(msIgG)抑制。

图9A为Western印迹，用所示浓度的IL-13于37℃处理HT-29人上皮细胞30分钟后，检测其中的磷酸化STAT6蛋白质。

图9B为流式细胞试验的柱状图，测量IL-13处理后磷酸化STAT6蛋白质的细胞水平。经IL-13处理的磷酸化STAT6染色强度的移动如浅色阴影线所示。

图9C为一组流式细胞试验的柱状图，测量次佳浓度的人IL-13和所示抗体处理后磷酸化STAT6蛋白质的细胞水平。IL-13和抗体处理的细胞如黑线所示。阴影柱状图表示未接受处理的细胞。除mAb13.2外，也测试了IL-13特异性非中和抗体(mAb13.8)和对照小鼠IgG1。

图10为显示了用蛔虫抗原攻击肺段后对猪蛔虫(Ascaris suum)致敏的猕猴(Cynomolgus monkeys)的BAL中检测到的嗜酸性粒细胞百分比的图表。攻击前24小时，向动物静脉施用mAb13.2(菱形)或不处理(圆圈)。三角形表示mAb13.2处理并在抗体施用后3个月再次用蛔虫攻击。利用去极化单侧散点分析通过流式细胞仪检测嗜酸性粒细胞。

图11A为显示了在ELISA测定中，未标记mAb13.2(菱形)或mAb13.2Fab片段(圆圈)能与生物素化mAb13.2竞争结合的图表。“无关抗体”(单克隆抗体mAb13.8，能结合于IL-13但不中和其活性)(星号)不能竞争结合。竞争物浓度以皮摩尔(pM)抗体或Fab表示。

图11B为显示了在ELISA测定中，未标记mAb13.2(菱形)或mAb13.2Fab片段(圆圈)能与生物素化mAb13.2竞争结合的图表。“无关抗体”(单克隆抗体mAb13.8，能结合于IL-13但不中和其活性)(星号)不能竞争结合。竞争物浓度以皮摩尔(pM)结合位点表示，其中认为每个完整IgG具有两个结合位点，而每个Fab片段具有一个结合位点。

图12A为显示了未标记mAb13.2(菱形)或mAb13.2 Fab片段(圆圈)抑制IL-13依赖性的TF1细胞分裂的图表。“竞争物浓度”是mAb13.2或mAb13.2 Fab片段的浓度，且所述浓度以pM竞争物结合位点表示，其中认为每个完整IgG具有两个结合位点，而每个Fab片段具有一个结合位点。

图12B为显示了未标记mAb13.2(菱形)或mAb13.2 Fab片段(圆圈)抑制人PBMC上IL-13 CD23的表达的图表。“竞争物浓度”是mAb13.2或mAb13.2 Fab片段的浓度，且该浓度以pM竞争物结合位点表示，其中认为每个完整IgG具有两个结合位点，而每个Fab片段具有一个结合位点。

图13为含有人IL-13cDNA插入物(hIL13coli)的表达载体pAL-981的DNA序列(SEQ ID NO：5)。下划线表示编码IL-13的cDNA序列。限制性位点Nde1(核苷酸位置2722)和Xba1(核苷酸位置3070)侧接该cDNA序列。

图14为人IL-13Rα1(Swiss-Prot登录号78552)的氨基酸序列(SEQID NO：12)。

图15为图示mAb13.2 Fab/IL-13/IL-13Rα1三聚复合物结构的带状图。

图16为图示IL-13和IL-13Rα1 Ig结构域1间相互作用的带状图。

图17为图示IL-13和IL-13Rα1 Ig结构域3间相互作用的带状图。

发明详述

X射线晶体学揭示了鼠单克隆抗IL-13抗体mAb13.2的抗原结合片段(Fab)的结构(见下表10)。X射线晶体学也揭示了人IL-13与mAb13.2Fab片段复合、人IL-13与mAb13.2 Fab片段及IL-13Rα1多肽片段复合的晶体结构(分别见下表11和12)。

图1A和1B提供了mAb13.2 Fab片段轻链和重链多肽的氨基酸序列信息。图2A和2B提供了人IL-13的氨基酸序列信息。图3提供了人IL-13/mAb13.2 Fab片段复合物晶体的结构信息。所述mAb13.2 Fab片段结合人IL-13的IL-14R(IL-4Rα)结合结构域，其中包括SEQ ID NO：4定义的氨基酸Ser7、Thr8、Ala9、Glul2、Leu48、Glu49、Ile52、Asn53、Arg65、Met66、Ser68、Gly69、Phe70、Cys71、Pro72、His73、Lys74和Arg86。

图14提供了人IL-13受体多肽——人IL-13Rα1的氨基酸序列信息。图15、16和17提供了人IL-13Rα1多肽/人IL-13/mAb13.2 Fab片段复合物晶体的结构信息。除上述人IL-13与mAb13.2 Fab片段之间的相互作用外，人IL-13与人IL-13Rα1多肽还形成两处接触，一处为与人IL-13Rα1多肽的Ig结构域1之间，另一处为与人IL-13Rα1多肽的Ig结构域3之间。与Ig结构域1的相互作用涉及SEQ ID NO：4定义的人IL-13中的Thr88、Lys89、Ile90和Glu91残基，以及SEQ ID NO：12定义的人IL-13Rα1多肽中Lys76、Lys77、Ile78和Ala79残基(见图16)。与Ig结构域3的相互作用涉及SEQ ID NO：4定义的人IL-13中的Arg11、Glu12、Leu13、Ile14、Glu15、Lys104、Lys105、Leu106、Phe107和Arg108残基，以及SEQ IDNO：12定义的人IL-13Rα1多肽中Ile254、Ser255、Arg256、Lys318、Cys320和Tyr321残基(见图17)。

一般可根据需要制备mAb13.2 Fab片段的晶体。一般而言，方法包括首先分离mAb13.2 Fab片段，然后形成含有所述mAb13.2 Fab片段的晶体。在某些实施方案中，可如下制备含有mAb13.2 Fab片段的晶体。用适当的蛋白水解酶(如木瓜蛋白酶)裂解完整的抗体，并将mAb13.2 Fab片段从Fc(可结晶片段)片段中分离出来。将分离的mAb13.2 Fab片段置于适当的溶液中，并结晶所述溶液。例如，溶液中可含有一种或多种聚合物(如聚乙二醇(PEG))、一种或多种盐(如硫酸钾)以及任选的一种或多种有机溶剂。可以通过多种方法使晶体生长，例如座滴或悬滴蒸汽扩散法。一般而言，可在约4℃至60℃的温度进行结晶(例如约4℃至45℃，例如约4℃、约15℃、约18℃、约20℃、约25℃、约30℃、约32℃、约35℃、约37℃)。例如，通过X射线衍射，可以得到描述mAb13.2 Fab片段晶体的结构数据。可以通过多种方法收集X射线衍射数据，以得到结构坐标。合适的X射线源包括旋转阳极和同步加速器源(如先进光源(ALS)，Berkeley，California；或先进光子源(APS)，Argonne，Illinois)。在某些实施方案中，用于产生衍射数据的X射线波长可为约0.5_至约1.6_(如约0.7_、约0.9_、约1.0_、约1.1_、约1.3_、约1.4_、约1.5_、约1.6_)。合适的X射线检测器包括二维探测器和/或电荷耦合器件(CCD)可用作为检测器。

一般而言，mAb13.2 Fab片段的晶体能够衍射X射线至分辨率为约3.5_或更小(例如约3.2_或更小、约3.0_或更小、约2.8_或更小、约2.5_或更小、约2.4_或更小、约2.3_或更小、约2.2_或更小、约2.1_或更小、约2.0_或更小、约1.9_或更小、约1.8_或更小、约1.7_或更小、约1.6_或更小、约1.5_或更小、约1.4_或更小)。在某些实施方案中，mAb13.2 Fab片段的晶体能够衍射X射线至分辨率为约1.6_至约2.5_(例如约1.8_至约2.2_)。

在某些实施方案中，mAb13.2 Fab片段的晶体为正交晶体，其空间群为P212121，且晶胞大小a＝54.4，b＝98.0，c＝108.5，且α＝β＝γ＝90℃。

一般可根据需要制备含有人IL-13和mAb13.2 Fab片段的复合物并结晶之。在某些实施方案中，方法如下。从DNA质粒表达人IL-13。所述表达可由启动子如诱导型启动子驱动。人IL-13可表达为具有合适标签的融合蛋白质(例如促进人IL-13从细胞中分离)，例如谷胱甘肽-S-转移酶(GST)、myc、HA、六聚组氨酸或FLAG标签。可以在引入至融合蛋白质的蛋白酶位点处裂解融合蛋白质，例如在多肽和标签之间的融合位点处或其附近。人IL-13在纯化前(例如在裂解多肽标签之前)或纯化后都可以与mAb13.2 Fab片段混合。在某些实施方案中，mAb13.2 Fab片段同样可以在纯化前和纯化后与人IL-13混合。在某些实施方案中，人IL-13与mAb13.2 Fab片段在溶液中混合，从而获取复合物的质谱数据、复合物的NMR数据或者用于生长复合物晶体。例如，溶液中可含有一种或多种盐(如钾盐)、一种或多种聚合物(如聚乙二醇(PEG))和/或一种或多种有机溶剂。可以通过多种方法使晶体生长，例如座滴或悬滴蒸汽扩散法。一般而言，可在约16℃至24℃进行结晶(如约17℃至23℃，或约18℃至21℃)。

通过X射线衍射，可以得到人IL-13/mAb13.2 Fab片段复合物晶体的结构信息。一般而言，人IL-13/mAb13.2 Fab片段复合物晶体能够衍射X射线至分辨率为约3.5_或更小(例如约3.2_或更小、约3.0_或更小、约2.8_或更小、约2.5_或更小、约2.4_或更小、约2.3_或更小、约2.2_或更小、约2.1_或更小、约2.0_或更小、约1.9_或更小、约1.8_或更小、约1.7_或更小、约1.6_或更小、约1.5_或更小、约1.4_或更小)。在某些实施方案中，人IL-13/mAb13.2 Fab片段复合物晶体能够衍射X射线至分辨率为约1.6_至约2.5_(例如约1.8_至约2.2_)。

在某些实施方案中，人IL-13/m_b13.2 Fab片段复合物晶体为立方体，其空间群为P213，晶胞大小a＝b＝c＝125.3，且α＝β＝γ＝90℃。复合物结构可分辨至分辨率为1.8_。

一般而言，可根据需要制备含有人IL-13、mAb13.2 Fab片段和人IL-13Rα1多肽的复合物并结晶之。在某些实施方案中，方法如下。在酵母菌菌株巴斯德毕赤酵母(Pichia pastoris)中从DNA质粒表达人IL-13Rα1多肽，从而糖基化表达的多肽。所述从DNA质粒的表达可由启动子驱动，如诱导型启动子。人IL-13Rα1多肽可表达为具有合适标签的融合蛋白质(例如辅助人IL-13Rα1多肽从细胞中分离)，例如谷胱甘肽-S-转移酶(GST)、myc、HA、六聚组氨酸或FLAG标签。可以在引入至融合蛋白质的蛋白酶位点处裂解融合蛋白质，例如在多肽和标签之间的融合位点处或其附近。人IL-13Rα1多肽与人IL-13混合形成复合物，随后通过用酶如内切糖苷酶H处理将该复合物多肽去糖基化。可在去糖基化复合物上添加mAb13.2 Fab片段，形成人IL-13Rα1多肽/人IL-13/mAb13.2 Fab复合物。

在某些实施方案中，人IL-13Rα1多肽、人IL-13与mAb13.2 Fab片段在溶液中混合，从而获取复合物的质谱数据、复合物的NMR数据或者用于生长复合物晶体。例如，溶液中可含有一种或多种盐(如钾盐)、一种或多种聚合物(如聚乙二醇(PEG))和/或一种或多种有机溶剂。可以通过多种方法使晶体生长，例如座滴或悬滴蒸汽扩散法。一般而言，可在约16℃至24℃进行结晶(如约17℃至23℃，或约18℃至21℃)。

通过X射线衍射，可以得到人IL-13Rα1多肽/人IL-13/mAb13.2 Fab片段复合物晶体的结构信息。一般而言，人IL-13Rα1多肽/人IL-13/mAb13.2 Fab片段复合物晶体能够衍射X射线至分辨率为约3.5_或更小(例如约3.2_或更小、约3.0_或更小、约2.8_或更小、约2.5_或更小、约2.4_或更小、约2.3_或更小、约2.2_或更小、约2.1_或更小、约2.0_或更小、约1.9_或更小、约1.8_或更小、约1.7_或更小、约1.6_或更小、约1.5_或更小、约1.4_或更小)。在某些实施方案中，人IL-13Rα1多肽/人IL-13/mAb13.2 Fab片段复合物晶体能够衍射X射线至分辨率为约1.6_至约2.5_(例如约1.8_至约2.2_)。

在某些实施方案中，人IL-13Rα1多肽/人IL-13/mAb13.2 Fab片段复合物晶体为立方体，其空间群为14，且晶胞大小a＝b＝164.9_，c＝74.8_，且α＝β＝γ＝90℃。复合物结构可分辨至分辨率为2.2_。

mAb13.2 Fab片段、人IL-13/mAb13.2 Fab片段复合物或人IL-13Rα1多肽/人IL-13/mAb13.2 Fab片段复合物晶体的X射线衍射数据可用于获取抗体或复合物中的原子结构坐标。这些结构坐标为Cartesian坐标，描述原子在三维空间中相对于复合物中其他原子的位置。例如，表10中列出的结构坐标为mAb13.2 Fab片段晶体的结构坐标。这些结构坐标描述了mAb13.2 Fab片段中原子彼此之间的位置关系。又例如，表11中列出的结构坐标为人IL-13/mAb13.2 Fab片段复合物晶体的结构坐标。这些结构坐标描述了人IL-13中原子彼此之间的位置关系、人IL-13中原子相对于mAb13.2 Fab片段中原子的位置以及mAb13.2 Fab片段中原子彼此之间的位置关系。再例如，表12中列出的结构坐标为人IL-13Rα1多肽/人IL-13/mAb13.2 Fab片段复合物晶体的结构坐标。这些结构坐标描述了人IL-13Rα1多肽中原子彼此之间的位置关系、人IL-13Rα1多肽中原子相对于人IL-13中原子的位置、人IL-13中原子彼此之间的位置关系、人IL-13中原子相对于mAb13.2 Fab片段中原子的位置以及mAb13.2 Fab片段中原子彼此之间的位置关系。

可以通过数学处理精修晶体的结构坐标，如通过反演或整数加减。这样的结构坐标为相对坐标。例如，描述mAb13.2 Fab片段中原子位置的结构坐标并不受表10中实际x、y和z坐标的具体限制。又例如，描述结合于mAb13.2 Fab片段的人IL-13中原子位置的结构坐标并不受表11中实际x、y和z坐标的具体限制。再例如，描述结合于mAb13.2 Fab片段及人IL-13Rα1多肽两者的人IL-13中原子位置的结构坐标并不受表12中实际x、y和z坐标的具体限制。

mAb13.2 Fab片段或人IL-13/mAb13.2 Fab片段复合物或人IL-13Rα1多肽/人IL-13/mAb13.2 Fab片段复合物的结构坐标可用于得到mAb13.2Fab片段、mAb13.2 Fab片段的片段、人IL-13、人IL-13片段、人IL-13Rα1多肽、人IL-13Rα1多肽片段、人IL-13/mAb13.2 Fab片段复合物或人IL-13Rα1多肽/人IL-13/mAb13.2 Fab片段复合物、或任一复合物片段的表示(例如二维表示或三维表示)。此类表示可用于多种应用，包括如呈现、鉴定及表征多肽活性位点。在某些实施方案中，三维表示可包括表10中mAb13.2 Fab片段的结构坐标±氨基酸中α碳原子的均方根差(约1.5_或更小，如约1.0_或更小，或约0.5_或更小)。在其他实施方案中，三维表示包括表11中人IL-13/mAb13.2 Fab片段的结构坐标±氨基酸中α碳原子的均方根差(约1.5_或更小，如约1.0_或更小，或约0.5_或更小)。在其他实施方案中，三维表示包括表12中人IL-13Rα1多肽/人IL-13/mAb13.2 Fab片段的结构坐标±氨基酸中α碳原子的均方根差(约1.5_或更小，如约1.0_或更小，或约0.5_或更小)。均方根差(rms偏差或rmsd)为均值方差算术平均值的平方根，是表示与结构坐标间偏差或变差的一种方式。氨基酸的保守性取代会导致分子表示的结构坐标落入所述的均方根差范围内。例如，两个多肽之间因为保守性氨基酸取代而彼此有别，其分子模型的主链原子坐标可落入所述rms偏差内，例如小于约1.5_(例如小于约1.0_，小于约0.5_)。多肽的主链原子包括α碳原子(Cα或CA)、羰基碳原子(C)以及酰胺氮原子(N)。

多种软件程序可对系列结构坐标进行图像表示，得到分子或分子复合物如mAb13.2 Fab片段或人IL-13/mAb13.2 Fab片段复合物或人IL-13Rα1多肽/人IL-13/mAb13.2 Fab片段复合物的表示。一般而言，此类表示应当准确反映(相对地和/或绝对地)结构坐标或来自结构坐标的信息，如要素间的距离或角度。所述表示可为二维图形，如立体二维图形或交互式二维显示(如能够展示分子或分子复合物不同侧面的计算机显示)，或交互式立体二维演示。例如，交互式二维显示的实例可以是能够旋转以展示多肽、多肽片段、复合物和/或复合物片段不同侧面的计算机显示。在有些实施方案中，所述表示为三维表示。例如，三维模型可为分子结构的物理模型(如球棍模型)。又例如，三维表示可以为分子结构的图像表示(例如计算机显示上出现的图画或图形)。当二维表示反映了三维信息时(如通过应用透视、阴影或通过离观察者更近的要素阻断离观察者更远的要素)，二维图形表示(如图画)可对应于三维表示。在有些实施方案中，可以在不止一个水平上建模表示。例如，如果三维表示中包括多肽如结合于mAb13.2 Fab片段的人IL-13，则可在一个或多个不同结构水平上表示该多肽，如一级结构(氨基酸序列)、二级结构(如α螺旋和β片层)、三级结构(整体折叠)，以及四级结构(寡聚状态)。也可在一个或多个不同结构水平上表示mAb13.2 Fab片段的重链和轻链多肽。表示可以包括不同水平的细节。例如，表示可包括蛋白质二级结构要素的相对位置，而不指明具体原子的位置。例如，更为详细的表示可以包括原子的位置。

在有些实施方案中，表示可含有除了原子在mAb13.2 Fab片段、人IL-13/mAb13.2 Fab片段复合物或人IL-13Rα1多肽/人IL-13/mAb13.2 Fab片段复合物中结构坐标以外的信息。例如，表示可以提供有关溶剂可及表面的形状、模型中原子的范德瓦尔斯(van der Waals)半径以及溶剂(如水)范德瓦尔斯半径的信息。其他可从表示中得到的特征包括如，静电势、大分子结构内部空间或口袋的定位，以及氢键和盐桥的位置。

通过包括利用mAb13.2 Fab片段、人IL-13、人IL-13Rα1多肽、人IL-13/mAb13.2 Fab片段复合物或人IL-13Rα1多肽/人IL-13/mAb13.2 Fab片段复合物表示的方法，可以鉴定或设计与mAb13.2 Fab片段、人IL-13或人IL-13Rα1多肽相互作用的物质。表示的例示性类型包括上文所讨论的表示。在有些实施方案中，表示可以为类似物多肽、多肽片段、复合物或复合物片段的表示。通过实施候选物质与表示间的计算机拟合分析，可以设计或鉴定与所述表示相互作用的候选物质。一般而言，物质为分子。其实例包括多肽、核酸(包括DNA或RNA)或小分子(如有机小分子)。物质可以为配体，且可作为，例如，激动剂或拮抗剂起作用。与多肽(如人IL-13、人IL-13Rα1多肽)相互作用的物质能够与多肽发生暂时或稳定的相互作用。此处提及的任一种作用力都可介导所述相互作用，包括如氢键、静电力、疏水相互作用以及范德瓦尔斯作用。

如上所述，X射线晶体学可用于获取mAb13.2 Fab片段、人IL-13/mAb13.2 Fab片段复合物或人IL-13Rα1多肽/人IL-13/mAb13.2 Fab片段复合物的结构坐标。不过，也可利用其他技术包括NMR技术得到此类结构坐标。通过光谱技术(如旋光散射(ORD)、圆二色谱(CD))、同源建模以及计算机方法(如包括来自分子力学或来自动力测定的数据的那些计算机方法)可得到附加的结构信息。

在某些实施方案中，X射线衍射数据可用于构建mAb13.2 Fab片段、人IL-13/mAb13.2 Fab片段复合物或人IL-13Rα1多肽/人IL-13/mAb13.2Fab片段复合物的电子密度图。所述电子密度图可用于得到mAb13.2 Fab片段、mAb13.2 Fab片段的片段、人IL-13或人IL-13片段、人IL-13Rα1多肽或人IL-13Rα1多肽片段、人IL-13/mAb13.2 Fab片段复合物或人IL-13Rα1多肽/人IL-13/mAb13.2 Fab片段复合物、或任一复合物片段的表示(例如二维表示或三维表示)。创建电子密度图一般涉及利用有关X射线散射相位的信息。例如，可通过从衍射数据或增补衍射试验中提取相位信息，完成电子密度图的构建。从X射线衍射数据中计算相位的方法包括(不限于)：多波长异常散射法(MAD)、多对同晶置换(MIR)、多对同晶置换异常散射法(MIRAS)、单对同晶置换异常散射法(SIRAS)、倒易空间母液平滑((reciprocal space solvent flattening))、分子置换或者它们的组合。这些方法通过对天然蛋白质进行同晶结构修饰产生相位信息，例如通过加入重原子或改变已有重原子的散射强度，然后测量天然蛋白质及每一修饰情况下的衍射振幅。如果已知添加重原子的位置或其散射强度的改变，则可以通过求解一系列相位联立方程式确定每一衍射X射线的相位。可以利用计算机程序，例如SHELXS(Sheldrick，Institut Anorg.Chemie，Gottingen，Germany)鉴定重原子位点的位置，并可利用计算机程序如MOSFLM、SCALA、SOLOMON和SHARP(“The CCP4 Suite：Programs for Protein Crystallography，”Acta Crystallogr.Sect.D，54：905-921，1997；deLa Fortelle和Brigogne，Meth.Enzym. 276：472-494，1997)处理衍射数据。确定相位后就能构建复合物的电子密度图。

将电子密度图与多肽或复合物(例如含有结合于抗体的多肽的复合物)的三维模型进行比对，可利用电子密度图得到多肽、复合物、或多肽或复合物片段的表示。该排列过程产生了对比模型，显示计算的电子密度图与之前已知多肽或之前已知复合物模型的差异程度。然后通过一轮或多轮(例如2轮、3轮、4轮、5轮、6轮、7轮、8轮、9轮、10轮)完善对比模型，使其更好地拟合电子密度图。软件程序如CNS(Brunger等人，ActaCrystallogr.D54：905-921，1998)可用于完善这一模型。可以通过如R_work或R_free值测量对比模型的拟合质量。R_work或R_free值较小一般提示拟合更好。可以调整对比模型中的错误比对，提供精修的对比模型和更低的R_work或R_free值。这些调整可基于人IL-13、人IL-13Rα1、mAb13.2 Fab片段、已知多肽和/或已知复合物的相关信息。例如，此类信息包括估计的螺旋或β片层含量、疏水及亲水结构域、以及蛋白质折叠方式，这些信息可来自，例如，氨基酸序列、同源建模及质谱数据。例如，在使用已知结合配体的多肽的复合物模型的实施方案中，调整可包括用mAb13.2片段取代已知复合物中的配体。又例如，在某些实施方案中，调整可包括用人IL-13相应位点上的氨基酸取代已知多肽中的氨基酸。当调整使精修的对比模型达到与电子密度图的最佳拟合时，产生的模型即为确定的描述X射线数据来源的抗体或多肽或复合物(如人IL-13/mAb13.2 Fab片段复合物)。此类过程的方法公开于如Carter和Sweet编辑，“Macromolecular Crystallography”，Methods in Enzymology，277卷，B部分，New York：Academic Press，1997及其中的文章，例如Jones和Kjeldgaard，“Electron-Density MapInterpretation”第173页，以及Kleywegt和Jones，“Model Building andRefinement Practice”第208页。

在某些实施方案中，将根据X射线衍射数据得到的mAb13.2 Fab片段电子密度图与先前已确定的不同(但相似)抗体Fab片段(如2E8 Fab抗体片段，蛋白质数据库(Protein Databank)识别号12E8)的结构模型进行比对，可以得到mAb13.2 Fab片段的表示。随后将根据X射线衍射数据得到的人IL-13/mAb13.2 Fab片段复合物的电子密度图与先前已确定的mAb13.2 Fab片段的结构模型进行比对，可以得到所述复合物的表示。随后将根据X射线衍射数据得到的人IL-13Rα1多肽/人IL-13/mAb13.2 Fab片段复合物电子密度图，与先前已确定的人IL-13/mAb13.2 Fab片段的结构模型进行比对，可以得到人IL-13Rα1多肽/人IL-13/mAb13.2 Fab片段复合物的表示。

可编程使机器如计算机存储mAb13.2 Fab片段、人IL-13/mAb13.2Fab片段复合物或人IL-13Rα1多肽/人IL-13/mAb13.2 Fab片段复合物的结构坐标，同时还有能够在与所述机器连接的显示器上产生该结构坐标的三维图形表示的程序。或者或此外，可设计和/或使用软件系统以接受和存储结构坐标。所述软件系统能产生结构坐标的图像表示。所述软件系统也能进入外部数据库以鉴定与人IL-13或人IL-13Rα1具有相似结构特征的化合物(如多肽)，和/或鉴定一种或多种候选物质，所述候选物质的特征使其可与人IL-13或人IL-13Rα1相互作用。所述软件系统还能进入外部数据库，通过已知的mAb13.2 Fab片段和人IL-13Rα1结构及其与人IL-13的相互作用，鉴定与人IL-13或人IL-13Rα1相互作用的化合物。

具有含结构数据的存储器或含此类数据的软件系统的机器，有助于IL-13配体如激动剂或拮抗剂的合理设计或选择。例如，此类机器或软件系统有助于评估物质与人IL-13相连的能力、有助于建模与人IL-13结构或序列同源相关的化合物或蛋白质，或有助于评估物质干扰人IL-13生物活性的能力。人IL-13的生物活性可以为多肽于体内或体外在细胞或组织表面或内部激发的任何效应。人IL-13例示性的生物活性述于此处，如实施例1和2所示。

具有含结构数据的存储器或含此类数据的软件系统的机器，有助于IL-13Rα1配体如激动剂或拮抗剂的合理设计或选择。例如，此类机器或软件系统有助于评估物质与人IL-13Rα1多肽相连的能力、有助于建模与人IL-13Rα1多肽结构或序列同源相关的化合物或蛋白质，或有助于评估物质干扰人IL-13Rα1多肽生物活性的能力。人IL-13Rα1多肽的生物活性可以为多肽于体内或体外在细胞或组织表面或内部激发的任何效应。人IL-13Rα1例示性的生物活性述于此处，如实施例3所示。

所述机器能产生mAb13.2 Fab片段或mAb13.2 Fab片段的片段、人IL-13或人IL-13片段、人IL-13Rα1多肽或人IL-13Rα1多肽片段、人IL-13/mAb13.2 Fab片段复合物、人IL-13Rα1多肽/人IL-13/mAb13.2 fab片段复合物、或任一复合物片段的表示(如二维表示或三维表示)。例如，软件系统能使机器产生此类信息。所述机器可包括机器可读的数据存储介质，其中包括用机器可读数据编码的数据存储材料。所述机器可读数据可包括mAb13.2 Fab片段的原子或mAb13.2 Fab片段的片段的原子、人IL-13的原子或人IL-13片段的原子、人IL-13Rα1多肽的原子或人IL-13Rα1多肽片段的原子、人IL-13/mAb13.2 Fab片段复合物的原子、人IL-13Rα1多肽/人IL-13/mAb13.2 fab片段复合物的原子、或任一复合物的原子的结构坐标。含有数据存储材料的机器可读存储介质可包括常规计算机硬驱、软盘、DAT磁带、CD-ROM、DVD以及其他磁性介质、磁光介质、光介质及可适用于计算机的其他介质。所述机器也可具有工作存储器用于存储处理机器可读数据的指令，还可具有耦联于工作存储器及机器可读数据存储介质的中央处理器(CPU)，以将机器可读数据处理成所需的三维表示。最后，显示器可连接于CPU，从而可使用户看到三维表示。因此，当与带有使用数据指令所编程的机器(例如加载有一个或多个此处所述程序的计算机)一同使用时，所述机器能够显示此处所述的任一多肽、多肽片段、复合物或复合物片段的图形表示(如二维图形表示、三维图形表示)。

显示器(如计算机显示器)能够显示mAb13.2 Fab片段或mAb13.2 Fab片段的片段、人IL-13或人IL-13片段、人IL-13Rα1多肽或人IL-13Rα1多肽片段、人IL-13/mAb13.2 Fab片段复合物、人IL-13Rα1多肽/人IL-13/mAb13.2 fab片段复合物、或任一复合物片段的表示。表示中也可含有结合于人IL-13或人IL-13Rα1多肽的物质，或者用户可在人IL-13或人IL-13Rα1多肽的表示上添加某一物质的三维模型。所述物质可为人IL-13或人IL-13Rα1多肽的激动剂(如候选激动剂)或人IL-13或人IL-13Rα1多肽的拮抗剂(如候选拮抗剂)。在有些实施方案中，所述物质可为已知化合物或化合物片段。在某些实施方案中，该物质可为未知的化合物或未知化合物的片段。

用户可看到产生的表示。例如，通过改变此类多肽或多肽复合物的已有表示，可以产生mAb13.2 Fab片段或mAb13.2 Fab片段的片段、人IL-13或人IL-13片段、人IL-13Rα1多肽或人IL-13Rα1多肽片段、人IL-13/mAb13.2 Fab片段复合物、人IL-13Rα1多肽/人IL-13/mAb13.2 fab片段复合物、或任一复合物片段的表示。例如，当考虑复合物或复合物片段的新表示时，在抗体原子和人IL-13原子之间可以存在优选的距离或距离范围。又例如，当考虑复合物或复合物片段的新表示时，在人IL-13原子和人IL-13Rα1多肽原子之间可以存在优选的距离或距离范围。距离长于优选距离可能伴有物质与活性位点(例如IL-13多肽上的IL-13受体结合位点(如针对IL-13Rα1受体多肽或IL-4受体多肽))之间的弱相互作用。距离短于优选距离可能伴有会减弱物质及多肽间相互作用的排斥力。当原子间距离太短时可产生空间位阻。两个原子间过分接近会产生空间位阻，例如当两个原子间的距离短于其范德瓦尔斯半径之和时。若存在空间位阻，用户可以调整物质与人IL-13间的相对位置(例如物质的刚体平移或旋转)，直至解除空间位阻。用户可调整物质或物质附近的人IL-13构象，以解除空间位阻。也可通过改变物质结构来消除空间位阻，例如通过将“大基团”(如芳香环)改变为较小基团如甲基或羟基基团，或通过将刚性基团改变为能容纳不产生空间位阻的构象的柔性基团。静电力也会影响物质与多肽(例如多肽中与受体多肽如人IL-13Rα1多肽或人IL-4R多肽相互作用的部分)间的相互作用。例如，静电特性可为削弱物质和IL-13多肽间相互作用的排斥力。改变该物质的带电量(例如通过用中性基团取代带正电基团)能够解除静电排斥。实施类似的方法可以设计与人IL-13Rα1多肽相互作用的物质，例如在人IL-13Rα1多肽与人IL-13相互作用的邻近区域内。

在多肽/物质模型中评价影响mAb13.2 Fab片段和人IL-13间结合强度的作用力。与之类似，可在多肽/物质模型中评价影响人IL-13和人IL-13Rα1多肽间结合强度的作用力。例如，这些作用力可包括氢键、静电力、疏水相互作用、范德瓦尔斯相互作用、偶极-偶极相互作用、π-堆积力，以及阴离子-π堆积相互作用。用户能可视地评价这些作用力，例如通过观察氢键供体/受体对以适合氢键的距离和角度排列。基于所述评价，用户能改变模型从而发现人IL-13或人IL-13Rα1多肽与物质间更有利的相互作用。模型的改变可包括改变多肽的三维结构而不改变其化学结构，如通过改变氨基酸侧链的构象或主链二面角。模型的改变也可包括如上述改变物质的位置或构象。模型的改变还可包括改变物质的化学结构，如通过基团的取代、添加或去除。例如，若人IL-13上的氢键供体位于物质的氢键供体附近，则用户可以用氢键受体替代物质上的氢键供体。

可以调整物质和人IL-13间的相对位置或其构象，以寻找某一特定物质与IL-13多肽的最佳结合几何结构。与之类似，可以调整物质和人IL-13Rα1多肽间的相对位置，以寻找某一特定物质与IL-13Rα1多肽的最佳结合几何结构。最佳结合几何结构的特征在于，如有利的氢键距离和角度、最大的静电吸引力、最小的静电排斥力、疏水部分与水性环境间的隔离、及不存在空间位阻。最佳几何结构的计算能量可为人IL-13/抗体复合物或人IL-13/受体复合物的一组可能的几何结构中最低者。可通过如分子力学或分子动力学计算，确定最佳几何结构。

可以产生一系列结合于不同物质的人IL-13的表示。与之类似，可以产生一系列结合于不同物质的人IL-13Rα1多肽的表示。对于每一表示均可计算出一个评分。例如，所述评分能描述人IL-13与物质间预期的相互作用强度。所述评分能反映上述影响结合强度的因素之一。所述评分也可为反映不止一种因素的评分集合。根据其评分可以对不同物质进行排行。

可以自动的方式由机器(如计算机)实施物质设计中的步骤。例如，可以在机器内编程人IL-13或人IL-13Rα1多肽的表示及候选物质的表示。机器会找到每一候选物质与受体结合位点间的最佳结合几何结构，并计算出评分以确定其中哪些物质有可能与人IL-13或人IL-13Rα1多肽相互作用最强。

可以设计和/或执行软件系统以辅助这些步骤。用于产生表示或实施必要拟合分析的软件系统(如计算机程序)包括但不仅限于：Accelrys，Inc.(San Diego，CA)的MCSS、Ludi、QUANTA、Insight II、Cerius2、CHARMm和Modeler；TRIPOS，Inc.(St.Louis，MO)的SYBYL、Unity、FleXX和LEAPFROG；AUTODOCK(Scripps Research Institute，La Jolla，CA)、GRID(Oxford University，Oxford，UK)；DOCK(University of California，San Francisco，CA)；以及Flo⁺和Flo99(Thistlesoft，Morris Township，NJ)。其他有用的程序包括Openeye Scientific Software(Santa Fe，NM)的ROCS、ZAP、FRED、Vida和Szybki；Schrodinger，LLC(Portland，OR)的Maestro、Macromodel和Glide；MOE(Chemical Computing Group，Montreal，Quebec)、Allegrow(Boston De Novo，Boston，MA)、CNS(Brunger等人，Acta Crystall.Sect.D 54：905-921，1997)以及GOLD(Jones等人，J.Mol.Biol. 245：43-53，1995)。通过MOLSCRIPT、RASTER3D或PYMOL(Kraulis，J.Appl.Crystallogr. 24：946-950，1991；Bacon和Anderson，J.Mol.Graph. 6：219-220，1998；DeLano， The PYMOL Molecular Graphics System(2002)DeLano Scientific，San Carlos，CA)，结构坐标也可用于可视化人IL-13的三维结构。

例如，可通过筛选合适的数据库选择物质，可通过分析未结合的人IL-13或未结合的人IL-13Rα1多肽的空间构型和电势、结合适当的软件系统从头设计所述物质，和/或利用已知细胞因子配体的特性设计所述物质。可以测试所述物质阻断IL-13与IL-4R多肽(如IL-4Rα或IL-Rα1多肽)结合的能力。可设计结合人IL-13或人IL-13Rα1多肽的物质。所述方法可用于设计或选择人IL-13或人IL-13Rα1多肽的激动剂或拮抗剂。可以设计和/或执行软件系统以辅助数据库检索，和/或物质的选择和设计。

一旦物质得以设计或鉴定，可以获取或合成所述物质并进一步评估其对人IL-13活性或人IL-13Rα1多肽活性的作用。将所述物质接触人IL-13并测定IL-13生物活性、或将所述物质接触人IL-13Rα1并测定IL-13Rα1生物活性，可评估所述物质。评估物质的方法包括体外或体内的活性测定。活性测定可为如基于细胞的测定。根据物质对人IL-13或人IL-13Rα1多肽的作用，所述物质可作用为人IL-13或人IL-13Rα1多肽活性的激动剂或拮抗剂。激动剂会使人IL-13或人IL-13Rα1多肽具有相同或相似的活性，而拮抗剂会抑制人IL-13或人IL-13Rα1多肽的正常功能。当存在抗IL-13抗体(如mAb13.2或mAb13.2 Fab)或人IL-13受体(例如，IL-4R多肽如人IL-4Rα多肽，或IL-13R多肽如人IL-13Rα1多肽)时，可以使物质接触人IL-13以确定所述物质是否抑制抗体或受体与人IL-13多肽的结合。在某些实施方案中，所述物质会抑制一类受体与人IL-13的结合，但不会抑制另一类受体的结合。例如，某物质能抑制人IL-13多肽与人IL-4R多肽(如IL-4Rα链)的结合，但不会抑制其与人IL-13Rα1多肽结合。与之类似，与之不同的物质能抑制人IL-13与IL-13Rα1多肽的结合，但不抑制其与人IL-4R多肽的结合。在另一个实施方案中，所述物质会抑制IL-13多肽与人IL-4R多肽(如IL-4Rα链)及人IL-13Rα1多肽的结合。使含有结合于所鉴定物质的人IL-13的晶体生长，并通过X射线晶体学确定其结构。基于第一物质与人IL-13的相互作用，可以设计或鉴定第二物质。多种分子分析和合理的药物设计技术进一步公开于如美国专利号5,834,228、5,939,528和5,856,116中，以及PCT申请号PCT/US98/16879(公布为WO 99/09148)中。

虽然已描述了某些实施方案，其他实施方案也包括在内。

例如，虽然已描述了涉及人IL-13、mAb13.2 Fab片段以及人IL-13Rα1多肽的实施方案，更一般而言，可以使用任何IL-13多肽、任何IL-13Rα1多肽，和/或任何抗IL-13抗体。

例如，虽然已描述了涉及人IL-13和人IL-13Rα1多肽的实施方案，更一般而言，可以使用任何IL-13多肽和任何IL-13Rα1多肽。例如，IL-13多肽或IL-13Rα1多肽可来自非哺乳动物或哺乳动物物种。非人哺乳动物实例包括，非人灵长类(例如猴或猿)、小鼠、大鼠、山羊、奶牛、公牛、猪、马、绵羊、野猪、海獭、猫或狗。非哺乳动物物种实例包括鸡、火鸡、虾、鳄或鱼。

此外，IL-13多肽或IL-13Rα1多肽一般为全长的成熟多肽，包括IL-13多肽或IL-13Rα1多肽的任一同工型或加工形式的全长氨基酸序列。同工型为一级结构不同的蛋白质若干多重形式之一。全长IL-13为蛋白质的前体形式。全长IL-13具有一个信号肽裂解位点。IL-13多肽可为加工后多肽，如裂解信号肽后的IL-13多肽。

人IL-13多肽一般具有至少一个可与受体多肽(例如IL-4R多肽、IL-13α1多肽)相互作用的活性位点。IL-13多肽可含有可与2个不同受体多肽相互作用的3个活性位点。抗IL-13抗体能够结合至少一个这些活性位点。一般而言，活性位点中可包括受体多肽结合位点，或磷酸化、糖基化、烷基化、酰基化或其他共价修饰位点。活性位点中可包括实际结合位点邻近的附属结合位点，后者可能会与配体相互作用而影响活性。人IL-13多肽的活性位点可包括SEQ ID NO：4的氨基酸。例如，人IL-13多肽的活性位点可包括SEQ ID NO：4氨基酸序列中定义的Ser7、Thr8、Ala9、Glu12、Leu48、Glu49、Ile52、Asn53、Arg65、Ser68、Gly69、Phe70、Cys71、Pro72、His73、Lys74和Arg86中的一个或多个氨基酸(图2B)。在某些实施方案中，物质可在约2.0_或更小(例如，约1.5_或更小、约1.0_或更小)距离内与SEQ ID NO：4氨基酸序列定义的IL-13中Glu49、Asn53、Gly69、Pro72、His73、Lys74和Arg86的一个或多个氨基酸相互作用。或者，人IL-13多肽的活性位点可包括SEQ ID NO：4定义的氨基酸序列中Arg11、Glu12、Leu13、Ile14、Glu15、Lys104、Lys105、Leu106、Phe107和Arg108中一个或多个氨基酸。又或者，人IL-13多肽的活性位点可包括SEQ ID NO：4氨基酸序列中定义的Thr88、Lys89、Ile90和Glu91一个或多个氨基酸。人IL-13多肽可包括上述1个、2个或所有3个活性位点。

人IL-13Rα1多肽一般具有至少一个与多肽配体(如人IL-13多肽)相互作用的活性位点。抗IL-13Rα1抗体能够结合至少一个这些活性位点。一般而言，活性位点中可包括多肽配体结合位点，或磷酸化、糖基化、烷基化、酰基化或其他共价修饰位点。活性位点中可包括实际结合位点邻近的附属结合位点，后者可能会与配体相互作用而影响活性。人IL-13Rα1多肽的活性位点可包括SEQ ID NO：12的氨基酸。例如，人IL-13Rα1多肽的活性位点可包括SEQ ID NO：12氨基酸序列定义的Ile254、Ser255、Arg256、Lys318、Cys320及Tyr321中一个或多个氨基酸残基。或者，人IL-13Rα1多肽的活性位点可包括SEQ ID NO：12氨基酸序列定义的Lys76、Lys77、Ile78及Ala79中一个或多个氨基酸残基。人IL-13Rα1多肽可具有上述活性位点之一或兼而有之。

人IL-13多肽、人IL-13Rα1多肽及抗IL-13抗体如mAb13.2 Fab的重链和轻链中的氨基酸编号可能与此处所列有所不同，其中可含有可产生相同三维结构的某些保守性氨基酸取代、添加或缺失，所述三维结构定义于表10，±主链原子均方根差(小于1.5_)；或定义于表11，±主链原子均方根差(小于1.5_)；或定义于表12，±主链原子均方根差(小于1.5_)。例如，人IL-13处理多肽的编号可能与图2B所示的有所不同，而该IL-13序列可能含有保守性氨基酸取代但仍产生由表11坐标定义、图3图示的相同结构，或由表12坐标定义、图15、16及17图示的相同结构。通过查看相关氨基酸序列或利用可购买的同源性软件程序(例如MODELLAR，MSI，San Diego，CA)，可以容易鉴定其他同工型或类似物中相应的氨基酸及保守性取代。

类似物为具有保守性氨基酸取代的多肽。保守性取代为功能上或结构上等同于被取代氨基酸的氨基酸取代。保守性取代可包括将氨基酸换为另一种与被取代氨基酸极性相似、空间排列相似、或属于同一类型(例如疏水、酸性或碱性)的氨基酸。保守性取代可包括那些在鉴定和设计与多肽(如IL-13多肽、IL-13Rα1多肽)相互作用的物质时，以及分子置换分析和/或同源性建模中，对抗IL-13抗体或人IL-13多肽/抗IL-13抗体复合物或人IL-13Rα1多肽/人IL-13多肽/抗IL-13抗体复合物的三维结构无重要影响的取代。

虽然已描述了小鼠抗IL-13抗体的实施例，更一般而言，可使用任何抗IL-13抗体。例如，抗IL-13抗体可来自人、小鼠、大鼠、仓鼠、兔、山羊、马或鸡。

又例如，虽然已描述了由某种方法产生抗IL-13抗体的实施方案，也可使用其他方法。例如，通过首先用重组或天然人IL-13免疫雌性BALB/c小鼠制备多克隆抗血清，可以产生抗IL-13抗体。可利用如ELISA的测定筛查血清与人IL-13的结合。将小鼠中表现出高血清抗体效价的脾细胞与骨髓瘤细胞系[如P3X63_AG8.653骨髓瘤细胞系(ATCC，Manassas，VA)]融合，并接种于选择性培养基内。通过有限稀释能够在多轮亚克隆后分离出融合株，并筛查融合株中对人IL-13有结合亲和力抗体的产生。抗IL-13抗体可为多克隆或单克隆。结合IL-13的抗体可为抗体片段，例如Fab片段。

一般而言，完整抗体(也称之为免疫球蛋白)是由两条各约25kDa的轻(L)链和两条各约50kDa的重(H)链组成的四聚糖基化蛋白质。每条轻链由N-端可变(V)结构域(VL)和恒定(C)结构域(CL)组成。每条重链由N-端可变结构域(VH)、3或4个恒定结构域(CH)，以及铰链区组成。距离VH最近的CH结构域记作CH1。VH和VL结构域含有4个相对保守的序列，称为构架区，构成3个高度可变序列(互补决定区，CDR)的框架。CDR中含有负责与抗原特异性相互作用的大部分残基。CDR被称作CDR1、CDR2和CDR3。相应地，重链的CDR组成部分称为H1、H2和H3，而轻链的CDR组成部分称为L1、L2和L3(见如表4)。不同类型免疫球蛋白的亚基结构和三维构象为本领域公知。关于抗体结构综述，见Antibodies：A Laboratory Manual，Cold Spring Harbor Laboratory，编辑Harlow等人(1988)。最小的抗原结合片段为由VH和VL结构域组成的Fv(可变片段)。Fab片段(抗原结合片段)由通过二硫键在恒定区间共价连接的VH-CH1和VL-CL结构域组成。

因此，本申请的一方面描述了结合和/或中和IL-13的抗体或其抗原结合片段。所述抗体或其片段也可为人、人源化、嵌合或体外生成的抗体。在一个实施方案中，抗IL-13抗体或其片段为人源化抗体。所述抗体包括一个或多个CDR，所述CDR的主链构象如表10所述CDR±均方根差(RMSD)(不大于1.5、1.2、1.1或1.0_)、如表11者±均方根差(RMSD)(不大于1.5、1.2、1.1或1.0_)，或如表12者±均方根差(RMSD)(不大于1.5、1.2、1.1或1.0_)。例如，轻链可变结构域的1个、2个或3个CDR(例如，具体为CDR1，或至少2个CDR如CDR1和CDR3、CDR1和CDR2，或所有3个CDR)相对于这些结构，其RMSD不大于1.5、1.2、1.1或1.0_。在一个实施方案中，抗体或其抗原结合片段包括可变结构域，其整体的主链构象如表10所述CDR±均方根差(RMSD)(不大于1.5、1.2、1.1或1.0_)、如表11者±均方根差(RMSD)(不大于1.5、1.2、1.1或1.0_)，或如表12者±均方根差(RMSD)(不大于1.5、1.2、1.1或1.0_)。可变结构域也可与此处所述抗体(如在CDR区域和/或构架区)具有至少70％、80％、85％、87％、90％、92％、93％、95％、96％、97％、98％或99％的同一性。所述抗体可用于如此处所述的治疗方法中。

例如，抗IL-13抗体公开于递交于2004年6月9日的美国临时专利申请号60/578,473、递交于2004年6月22日的美国临时专利申请号60/581,375，以及递交于与此同日的美国专利申请号＿＿[律师卷号：AM101493](Kasaian等人)，均在此处引用作为参考。

以下实施例为举例说明性的，而不旨在限制。

实施例

实施例1.mAb13.2的产生和功能分析

为产生识别IL-13的抗体，用重组人IL-13(R&D Systems，Minneapolis，MN)免疫雌性BALB/c小鼠，制备多克隆抗血清。利用ELISA筛查血清与人IL-13的结合。将小鼠中表现出高血清抗体效价的脾细胞与P3X63_AG8.653骨髓瘤细胞系(ATCC，Manassas，VA)融合，并接种于选择性培养基内。通过有限稀释用3轮亚克隆分离出融合株，并筛查融合株中对人IL-13有结合亲和力抗体的产生。3种单克隆抗体能够结合IL-13并中和和/或抑制其生物活性。单克隆抗体mAb13.2(IgG1κ)为进一步分析的对象。

进行若干测定以证实鼠单克隆抗体mAb13.2与人IL-13的结合具有高度的亲和力与特异性。首先，Biacore分析证实mAb13.2起效快、消失慢，并与人IL-13高亲和力结合(图4)。

ELISA测定显示mAb13.2结合所有测试的人IL-13形式，包括来自脐带血T细胞的天然IL-13(图5)。为实施重组人IL-13的测定，用抗FLAGM2抗体包被ELISA板。用生物素化mAb13.2及链霉亲和素-过氧化物酶检测重组FLAG标记的人IL-13。分离自丝裂原活化、TH2偏移的脐带血单核细胞的天然人IL-13以及重组人IL-13能够竞争这一结合(图5)。重组鼠IL-13不能竞争与mAb13.2的结合。非标记mAb13.2和非标记mAb13.2 Fab也能与生物素化mAb13.2竞争对flag标记的IL-13的结合(图11A)。IL-13特异性非中和单克隆抗体mAb13.8不能与生物素化mAb13.2结合竞争。

利用TF1生物检测、人外周血单核细胞以及人外周血B细胞，证实mAb13.2体外中和IL-13生物活性的能力。在IL-13的次佳浓度下，可使人红白血病TF1细胞系的细胞增殖为IL-13依赖性。去除TF1细胞系中的细胞因子，然后将其暴露于含浓度各异的纯化鼠mAb13.2或可溶性抑制剂rhuIL-13Rα2的次佳浓度(3ng/mL)重组人IL-13中。孵育细胞3天，最后4小时内根据液体闪烁计数加入3H-胸苷。在次佳IL-13浓度下(3ng/mL)，mAb13.2会引发对TF1增殖的剂量依赖性抑制(图6及图12A)。该效应的IC₅₀为250pM，与rhuIL-13Rα2的IC₅₀相当。mAb13.2 Fab也抑制人PBMC中的CD23表达。

人PBMC通过以剂量依赖性方式提高细胞表面低亲和力IgE受体(CD23)的表达，而对IL-13或IL-4产生应答(见图7A)。因此，使用单核细胞(CD11b⁺)证实mAb13.2中和IL-13生物活性的能力。在所示浓度纯化鼠mAb13.2中的存在下，用1ng/mL重组人IL-13(图7B)或IL-4(图7C)处理CD11b⁺单核细胞12小时。然后收集细胞并用CyChrome标记的抗CD11b抗体及PE标记的抗CD23抗体染色之。利用流式细胞术检测标记。mAb13.2抑制了IL-13诱导的CD23表达(图7B；也见图12B)，但不抑制IL-4诱导的CD23表达(图7C)。

也利用人外周血B细胞中IL-13诱导IgE生成的模型，测试了mAb13.2的作用。在IL-13和T细胞丝裂原即植物血凝素(PHA)的作用下，人B细胞发生Ig同种型的转换重组形成IgE，从而使培养物内IgE水平更高。这一效应可表现为产IgE的B细胞频度增加。为检查mAb13.2对B细胞中IL-13依赖性的IgE产生的作用，以自体辐照的PBMC为饲养细胞，将来自健康供者的PBMC培养于微量滴定板孔中，并用PHA和IL-13刺激之。3周后，用ELISA测定每一孔的IgE。PHA+IL-13增加了产生IgE的B细胞克隆的频度。这一效应被mAb13.2抑制，但并不被mAb13.8(结合IL-13但不中和)或无关鼠IgG所抑制。mAb13.2有效阻断了IL-13对培养的B细胞的这一效应(图8)。

最后，检查对信号转导和转录激活因子(STAT)6磷酸化的作用，测试mAb13.2阻断对IL-13的早期细胞应答能力。当IL-13与其细胞表面受体相互作用时，STAT6发生二聚化、磷酸化，并从胞质中转位至细胞核，在核内它激活细胞因子应答性基因的转录(Murata等人，J.Biol.Chem.270：30829-36，1995)。抗磷酸化STAT6的特异性抗体能通过Western印迹或流式细胞术，在暴露于IL-13 30分钟内检测这一激活。为测试mAb13.2对IL-13依赖性STAT6磷酸化的作用，于37℃用所示浓度的IL-13处理HT-29人表皮细胞系的细胞30分钟。通过Western印迹(图9A)或流式细胞术(图9B和9C)，检测细胞裂解物中的磷酸化STAT6。在图9B所示的试验中，用饱和浓度的IL-13于37℃处理细胞30分钟，然后固定、透化，并以Alexa-Fluor 488标记的抗磷酸化STAT6的mAb染色之。在图9C所示的试验中，有或无抗体时用次佳浓度的IL-13处理细胞，如上述固定并染色。流式细胞术结果显示mAb13.2阻断了STAT6磷酸化，而mAb13.8及对照鼠IgG1无作用。

实施例2：鼠单克隆抗体mAb13.2体内中和IL-13生物活性

利用对猪蛔虫(Ascaris suum)天然过敏的猕猴的抗原诱导气道炎症模型，测试鼠mAb13.2体内中和IL-13活性的能力。在该模型中，用猪蛔虫抗原攻击过敏猴，导致炎症性细胞特别是嗜酸性粒细胞流入气道。为测试mAb13.2阻断这一细胞聚集的能力，在用蛔虫抗原攻击前24小时施用抗体。在攻击当天，从左侧肺脏内获取基线灌洗样品。然后经气管内灌注抗原入右侧肺脏。24小时后，灌洗右肺，且将静脉用腹水8mg/kg纯化的mAb13.2处理的动物的支气管肺泡灌洗液(BAL)，与未处理动物的BAL液进行比较。5只未处理动物中有4只的嗜酸性粒细胞在攻击后增加，相比而言，6只用mAb13.2处理的动物中有1只增加(图10)。未处理组的BAL嗜酸性粒细胞百分比显著提高(p＜0.02)，但抗体处理组并非如此。这些结果证实mAb13.2有效阻断了过敏动物在过敏原攻击时的气道嗜酸性粒细胞增多。

小鼠mAb13.2在猴体内的平均血清半衰期小于1周。在3个月时间点时，当血清中的所有mAb13.2已消失时，用猪蛔虫再次攻击mAb13.2处理的动物，以确认这些受试者的猪蛔虫反应性。处理组6只猴子中有2只无应答。

实施例3：鼠单克隆抗体mAb13.2结合于IL-13中通常结合IL-4Rα的区域

由IL-13Rα1和IL-4Rα链组成的受体复合物介导IL-13生物活性。细胞因子首先以相对低亲和力与细胞表面的IL-13Rα1发生相互作用。然后该复合物募集IL-4Rα形成高亲和力受体(Zurawski等人，EMBO J.12：2663，1993；Zurawski等人，J.Biol.Chem. 270：23869，1995)。经IL-4Rα链的信号转导涉及STAT6的磷酸化，可将此作为对IL-13的早期细胞应答之一进行监测(Murata等人，J.Biol.Chem. 270：30829-36，1995)。若干方法如表位作图、X射线晶体学以及Biacore分析可用于阐释鼠mAb13.2抗体与人IL-13间的相互作用，并进一步确定该抗体IL-13中和效应的基础。

表位作图和X射线晶体学分析提示，mAb13.2结合于IL-13螺旋C的C端区域，即IL-4R结合区域(见下文)。为证实该分析，用Biacore芯片分析mAb13.2和IL-13间的相互作用。通过若干形式完成该分析。其一，将IL-4R与Biacore芯片结合，并使预结合于IL-13Rα1的IL-13复合物流过芯片。可证实不存在mAb13.2时形成了三分子复合物。然而，向预结合于IL-13Rα1的IL-13混合物中加入mAb13.2，阻止了与芯片上IL-4R的结合。其二，将mAb13.2固化于芯片，并加入液相的结合IL-13。虽然发现有IL-13Rα1与结合的IL-13相互作用，但未检测到IL-4R与结合的IL-13相互作用。其三，已经证实mAb13.2能结合与芯片固化IL-13Rα1-Fc或IL-13Rα1单体结合的IL-13。这些观测结果提示mAb13.2不会抑制IL-13与IL-13Rα1的相互作用，但破坏了IL-13Rα1与IL-4Rα的相互作用。这一破坏会阻止IL-13信号转导复合物的形成。这些发现提供了该抗体中和活性的模型。

体外证实mAb13.2与IL-13及IL-13Rα1的复合物，提示mAb13.2能够潜在地结合细胞表面受体结合的IL-13。为证实能否在受体结合IL-13饱和的条件下检测细胞结合的mAb13.2，于4℃向HT-29人表皮细胞系荷载IL-13，并测试抗体结合。流式细胞术未能检测到细胞结合的mAb。该观测结果连同mAb13.2为IL-13生物活性的有效中和物的证明，提示mAb13.2破坏了IL-13受体的正常功能。

实施例4：抗IL-13抗体mAb13.2 Fab片段的晶体结构

利用蛋白质A亲和柱纯化小鼠腹水来源的单克隆抗体mAb13.2。用蛋白A结合缓冲液(50mM Tris-HCl，500mM NaCl，pH 8.0)将小鼠腹水稀释两倍，并以0.2mm滤器单元过滤。将滤后溶液涂布用结合缓冲液4℃平衡的Poros蛋白质A柱(Applied Biosystems，Framingham，MA)。以结合缓冲液洗涤该柱，并用100mM甘氨酸(pH 3.0)洗脱IgG。即刻用1MTris-HCl(pH 8.0)中和洗脱的IgG。

用活化的木瓜蛋白酶(Sigma，St.Louis，MO)消化IL-13单克隆IgG，制备Fab片段。用消化缓冲液(50mM Tris-HCl，50mM NaCl，20mMEDTA和20mM半胱氨酸，pH 7.5)冰上稀释酶贮液，使木瓜蛋白酶终浓度为1mg/mL，活化木瓜蛋白酶。于37℃的木瓜蛋白酶消化缓冲液中将IgG与活化的木瓜蛋白酶以100∶1w/w的比例孵育7-8小时，裂解IgG。4℃于50mM Tris-HCl(pH 7.5)中透析过夜，终止反应。4℃将透析溶液装载到用50mM Tris-HCl(pH 7.5)平衡的串联Poros HS/蛋白质A柱上，去除木瓜蛋白酶及Fc片段。然后将含有Fab片段的串联柱流出液装载到用1mM磷酸钠及20mM Tris-HCl(pH 7.5)平衡的羟基磷灰石柱(Bio-Rad，Hercules，CA)上，并于25℃用1mM至125mM的磷酸钠梯度液洗脱。洗脱的Fab片段溶液在50mM Tris-HCl(pH 8.0)、4℃透析过夜。透析后，将该溶液置于用50mM Tris-HCl(pH 8.0)平衡的Poros HQ柱上。收集流出液，并加入硫酸铵调整终浓度为1.5M，然后装载到聚丙烯天冬酰胺柱上(Nest Group，Southborough，MA)。25℃用1.5至0M的硫酸铵梯度液从柱上洗脱Fab片段。于50mM Tris-HCl(pH 8.0)、4℃透析该蛋白质过夜。

测试了分离的mAb13.2抗体和mAb13.2 Fab片段抑制IL-13生物活性的能力。在一个测定中，在ELISA测定中测试纯化的mAb13.2和mAb13.2 Fab片段与生物素化mAb13.2竞争结合的能力。用抗FLAG M2抗体包被ELISA板。通过生物素化mAb13.2和链酶亲和素-过氧化物酶检测与FLAG-人IL-13的结合。完整的抗体及Fab片段均能竞争这一结合，而IL-13特异性非中和抗体mAb13.8不能竞争该结合(图11A及11B)。

在其他测定中，测试纯化的mAb13.2和mAb13.2 Fab片段抑制IL-13依赖性TF1细胞增殖以及PBMC中IL-13依赖性CD23表达的能力。如实施例1所述，将TF1细胞与3ng/mL重组人IL-13一起孵育。用浓度递增的纯化mAb13.2或mAb13.2 Fab处理细胞，并如上所述监测细胞增殖。完整抗体及Fab片段都抑制IL-13依赖性TF1细胞增殖(图12A)。为测试分离的蛋白质对CD23表达的作用，如实施例1所述，将PBMC与1ng/mL重组人IL-13一起孵育。用浓度递增的mAb13.2或mAb13.2 Fab处理单核细胞，并如上所述用流式细胞术监测CD23的表达。纯化的完整抗体及纯化的Fab片段各自都能抑制IL-13依赖性CD23表达(图12B)。

为进行结晶，在50mM Tris(pH 8.0)及50mM NaCl的溶液中制备浓度为12.6mg/mL的纯化mAb13.2 Fab。将1μl蛋白质溶液与1μl结晶溶液(20％PEG 3350，200mM K₂SO₄)(Hampton Research，Aliso Viejo，CA)混合，约18℃通过悬滴蒸汽扩散法形成晶体。

利用ADSC量子-4CCD探测器，在先进光源(ALS)(Berkley，CA)光束5.0.2处采集mAb13.2 Fab片段的晶体数据。每套数据均使用-180℃玻璃化的单个晶体。利用DENZO和Scalepack(Otwinowski和Minor，MethodsEnzymol. 276：307-326，1997)处理数据，数据采集及数据精修的统计数据分别如下表1和表2所示。

表1.数据采集和相位确定的统计数据

数据采集	mAb13.2 Fab	mAb13.2/IL-13 Fab
数据采集	mAb13.2 Fab	mAb13.2/IL-13 Fab	晶体系统	正交晶体	立方晶体
空间群	P2₁2₁2₁	P2₁3	晶体系统	正交晶体	立方晶体
空间群	P2₁2₁2₁	P2₁3	晶胞大小	a＝54.442，b＝97.961，c＝108.469，α＝β＝γ＝90.0°	a＝b＝c＝125.261，α＝β＝γ＝90.0°
数据采集温度	-180℃	-180℃	晶胞大小	a＝54.442，b＝97.961，c＝108.469，α＝β＝γ＝90.0°	a＝b＝c＝125.261，α＝β＝γ＝90.0°
数据采集温度	-180℃	-180℃	晶体数	1	1
射线源	ALS，Berkeley，CA	ALS，Berkeley，CA	晶体数	1	1
射线源	ALS，Berkeley，CA	ALS，Berkeley，CA	波长(_)	λ＝1.0_	λ＝1.0_
分辨率范围(_)	50-2.8_	50-1.8_	波长(_)	λ＝1.0_	λ＝1.0_
分辨率范围(_)	50-2.8_	50-1.8_	最大分辨率(_)	2.8_	1.8_
R_merge ^a(％)	8.2％(38.4％)	6.7％(48.6％)	最大分辨率(_)	2.8_	1.8_
R_merge ^a(％)	8.2％(38.4％)	6.7％(48.6％)	完成％	100％(100％)	99.9％(99.0％)
总反射(total refletions)	98,254	561,539	完成％	100％(100％)	99.9％(99.0％)
总反射(total refletions)	98,254	561,539	唯一反射(unique refletions)	14,903	57,656
I/σ(I)	23.3(4.8)	26.6(2.8)	唯一反射(unique refletions)	14,903	57,656

^aR_merge＝∑|I_h-<I_h>|/∑I_h，其中<I_h>为对称等效(symmetry equivalents)的平均强度。括号内的数字反应了最后一个壳层(last shell)的统计数据。

表2.结构精修的统计数据

数据采集	mAb13.2 Fab	mAb13.2 Fab/IL-13
数据采集	mAb13.2 Fab	mAb13.2 Fab/IL-13	分子置换模型	2E8 Fab(12E8.pdb)	mAb13.2 Fab；IL-13的溶液结构b
最大分辨率(_)	2.8_	1.8_	分子置换模型	2E8 Fab(12E8.pdb)	mAb13.2 Fab；IL-13的溶液结构b
最大分辨率(_)	2.8_	1.8_	R_work ^a(％)	25.9％	20.3％
R_free(％)	30.7％	23.5％	R_work ^a(％)	25.9％	20.3％

^aR_work＝∑||F_obs|-|F_calc||/∑|F_obs|，R_free与R_work等效，但是从精修过程省略的反射中随机选择5％计算得到。

^bMoy等人，J.Mol.Biol.310：219-230，2001。

利用程序AMORE(Navaza，Acta Crystallogr. A50：157-163，1994)，通过分子置换求解mAb13.2 Fab的结构。使用单克隆2E8 Fab抗体片段的结构(PDB代码12E8)作为探针。在精修前，随机选择5％的数据并命名为R_free测试系列，以监测精修进程。然后在QUANTA(Accelrys，San Diego，CA)中应用一系列省略图重建mAb13.2 Fab的结构。经历6轮CNS(Brunger等人，Acta Crystallogr. D54：905-921，1998)精修和QUANTA重建后，精修集中形成了R_晶体为25.9％、R_free为30.7％的含mAb13.2 Fab和41个水分子的模型。该结构精修统计数据如表2所示。晶体结构坐标见表10。

实施例5.mAb13.2 Fab/IL-13复合物的晶体结构

纯化重组IL-13(Swiss-Prot登录号P35225)及mAb13.2 Fab用于结晶。如下纯化重组IL-13。使用大肠杆菌K12菌株GI934表达人IL-13。GI934为GI724(LaVallie等人，Bio/Technology 11：187-193，1993)的ilvG衍生物，其两个大肠杆菌蛋白酶ompT和ompP中含有特定缺失。具体而言，该菌株含有稳定整合于染色体ampC基因座中的噬菌体l阻遏物(cI)基因。cI基因受合成的鼠伤寒沙门氏菌(Salmonella typhimurium)trp启动子的转录性调控。大肠杆菌表达载体pAL-981为pAL-781(Collins-Racie等人，Bio/Tchnology 13：982-987，1995)的衍生物，用作人IL-13表达载体的构建基础。

从合成的寡核苷酸双链体产生人IL-13的cDNA，所述双链体设计具有人IL-13cDNA(登录号NM_002188)的沉默性改变，从而最适于大肠杆菌密码子使用并提高基因5’端的AT含量。使用对应于人IL-13氨基酸(SEQ ID NO：3)中氨基酸Gly21至Asn1323的3组互补性合成寡核苷酸双链体(图2A)构建人IL-13的成熟区，即加工后IL-13的氨基酸序列(SEQID NO：4)。最佳大肠杆菌互补性寡核苷酸双链体1为

5’-TATGGGTCCAGTTCCACCATCTACTGCTCTGCGTGAACTGATTGAAGAACTGGTTAACATCACCCAGAACCAGAAAGCTCCGCTGTGTAACGGTTCCATGGTTTGGTCCATCAACCTG-3’(SEQ ID NO：6)，其互补序列为

5’-CAGCGGTCAGGTTGATGGACCAAACCATGGAACCGTTACACAGCGGAGCTTTCTGGTTCTGGGTGATGTTAACCAGTTCTTCAATCAGTTCACGCAGAGCAGTAGATGGTGGAACTGGACCCA-3(SEQ IDNO：7)；双链体2为

5’-ACCGCTGGTATGTACTGTGCAGCTCTGGAATCCCTGATCAACGTTTCTGGTTGCTCTGCTATCGAAAAAACCCAGCGTATGCTGTCTGGTTTCTGCCCGCACAAAGTTTCCGCTGGTCAG-3’(SEQ ID NO：8)，其互补序列为

5’-GAGGAGAACTGACCAGCGGAAACTTTGTGCGGGCAGAAACCAGACAGCATACGCTGGGTTTTTTCGATAGCAGAGCAACCAGAAACGTTGATCAGGGATTCCAGAGCTGCACAGTACATAC-3’(SEQ ID NO：9)；而双链体3为

5’-TTCTCCTCTCTGCACGTTCGTGACACCAAAATCGAAGTTGCTCAGTTCGTAAAAGACCTGCTGCTGCACCTGAAAAAACTGTTCCGTGAAGGTCGTTTCAACTAATAAT-3’(SEQ ID NO：10)，其互补序列为

5’-CTAGATTATTAGTTGAAACGACCTTCACGGAACAGTTTTTTCAGGTGCAGCAGCAGGTCTTTTACGAACTGAGCAACTTCGATTTTGGTGTCACGAACGTGCAGA-3’(SEQ ID NO：11)。

分别磷酸化第一和第二双链体的互补链(底端)以及第二和第三双链体的顶端链。混合互补链，并将各双链体混合物加热至90℃，缓慢冷却以使双链体退火。第一及最后的双链体分别编码限制性内切酶NdeI及XbaI，从而可克隆入经NdeI、XbaI消化、凝胶纯化的表达载体pAL-981中。所有的限制性消化、寡核苷酸酶促磷酸化、DNA片段分离及连接均如Sambrook等人，1989.“Molecular Cloning，a Laboratory Manual，第二版，”Cold Spring Harbor Laboratory Press，Cold Spring Harbor，NewYork所述实施。将连接混合物转化入(LaVallie等人，Methods Mol Biol.205：119-140，2003)所述的电感受态GI934中。将这3组寡核苷酸双链体连入pAL-981，产生质粒pALHIL13-981。所有合成寡核苷酸在克隆入表达载体后经测序确认。

将产生的质粒pALHIL13-981转化入GI934。经验确定从质粒pALHIL13-981中产生人IL-13的培养物的最佳生长温度。发酵培养基包括1％酸水解酪素、1.75％w/v葡萄糖、50mM KH₂PO₄、15mM(NH₄)₂SO₄、30mM柠檬酸三钠.2H₂0、20mM MgSO₄、100μg/ml氨苄青霉素、DM微量金属(300μM FeCl₃、29μM ZnCl₃、36μM CoCl₂、25μMNa₂MoO₄、20μM CaCl₂、22μM CuCl₂、24μM H₃BO₃)，并用NH₄OH调节pH为7。将在30℃发酵培养基中生长的含pALHIL13-981的新鲜GI934培养物接种于10L发酵罐中，至A₅₅₀为0.00005。使发酵培养物30℃生长至A₅₅₀为1.2，然后将温度调整至37℃，并令培养物生长至A₅₅₀为7.5。起始由pL启动子诱导的蛋白质合成，并向培养物中加入色氨酸至500μg/ml，培养物于37℃生长4.25小时，然后通过离心收集细胞。表达载体的序列如图13所示(SEQ ID NO：5)。

蛋白质基本上为完全不可溶。用微流化剂破坏细胞，并收集不可溶的IL-13，将其以约2mg/mL的浓度溶解于50mM Ches(pH 9)、6M盐酸胍、1mM EDTA、20mM DTT中。将溶液稀释20倍至50mM Ches(pH9)、3M盐酸胍、100mM NaCl、1mM氧化谷胱甘肽中，并以十倍体积的20mM Mes(pH 6)透析两次。离心净化后，将IL-13吸收于SP-琼脂糖中，并用NaCl梯度的Mes缓冲液洗脱。通过大小排阻层析在含40mM磷酸钠和40mM NaCl的Superdex 75上进行最终纯化。

如实施例4所述纯化mAb13.2 Fab。

将Fab与IL-13以约1∶1的摩尔比混合，制备Fab:IL-13复合物。将IL-13(50μM，溶于40mM MES及40mM NaCl中，pH 6.0)和mAb13.2Fab(50μM，溶于50mM Tris.HCl中，pH 8.0)混合在一起，使最终复合物浓度为50μM。用以50mM Tris-HCl和300mM NaCl(pH 8.0)、25℃平衡的Superdex 75大小排阻柱(Amersham Biosciences，Piscataway，NJ)进一步纯化复合物。纯化复合物在50mM Tris-HCl及50mM NaCl，pH 8.0中透析，然后建立晶体。

为进行结晶，在50mM Tris(pH 8.0)和50mM NaCl溶液中制备浓度为11.3mg/mL的纯化mAb13.2 Fab/Il-13复合物。将1μl蛋白质溶液与1μl结晶溶液混合(20％PEG 3350，50mM ZnOAc)(Hampton Research，Aliso Viejo，CA)。通过悬滴蒸汽扩散法在18℃形成晶体。

利用ADSC量子-4CCD探测器，在先进光源(ALS)(Berkley，CA)光束5.0.2处采集mAb13.2 Fab/IL-13复合物的晶体数据。每套数据均使用-180℃玻璃化的单晶体。利用DENZO和Scalepack(Otwinowski和Minor，Methods Enzymol. 276：307-326，1997)处理数据，数据精修的统计数据如表2所示。晶体结构坐标见于表11。

利用同步辐射二元mAb13.2 Fab/IL-13复合物晶体可衍射至1.8_。利用程序AMORE通过分子置换求解该复合物的结构，并使用mAb13.2 Fab的晶体结构(述于实施例4)作为探针。在精修前，随机选择5％的数据并命名为R_free测试，以监测精修进程。然后在QUANTA(Accelrys，San Diego，CA)中应用一系列省略图重建mAb13.2 Fab的结构。在这一过程中，高度可变区附近见到了额外的密度，且这些区域随着每一轮重建而愈显清晰。重建Fab片段后，旋转IL-13的NMR结构(Moy等人，J.Mol.Biol.310：219-230，2001)进入高度可变区邻近密度。经历3轮CNS(Accelrys，SanDiego，CA)精修和QUANTA重建后，精修集中形成了R_晶体为20.3％、R_free为23.5％的含1分子mAb13.2 Fab、1分子IL-13、1分子醋酸分子、3个锌离子以及465个水分子的模型。该结构精修统计数据如表2所示。

在mAb13.2/IL-13晶体复合物中，Fab轻链的1-211残基可视，而残基212、213和214则在密度中不可视。对于重链而言，残基1-127以及133-210建模入密度，但没有发现残基128至132的密度。对于IL-13，残基7-21、26-78以及81-109可视，而残基1-6、22-25、79及80则较杂乱。由于X射线试验电子密度不足，数个残基被模型为较小的残基(见表5)。

来自结晶缓冲液的3个锌分子见于结合该结构。它们中无一参与IL-13与Fab分子间的相互作用。这些锌分子中有2个参与非对称单元以及蛋白质对称性相关拷贝中分子间的接触，因此对于该复合物的结晶至关重要。锌1配位于Fab轻链残基Glu27和Glu97，以及该轻链对称性相关拷贝中的残基Glu189和His193(氨基酸编号依据SEQ ID NO：1(图1A))。锌2配位于IL-13残基His84和Asp87，以及IL-13对称性相关拷贝中的残基Asp98和His102。锌3配位于IL-13残基Glu12和Glu15，其中水分子作为其他配体(氨基酸编号依据SEQ ID NO：4(图2B))。

与mAb13.2 Fab片段相互作用的IL-13残基位于螺旋C的C-末端(残基68-74)。图3图示了IL-13中Cα螺旋与抗体中CDR环间的相互作用。在Fab与IL-13残基Glu49、Asn53、Gly69、Pro72、His73、Lys74和Arg86间存在氢键相互作用。螺旋A的N末端尖端处于Fab片段的范德瓦尔斯范围内。这些相互作用总结于表3和4。

表3.IL-13与Fab 13.2间的H键相互作用

IL-13^a			Fab 13.2
IL-13^a			Fab 13.2					残基	原子	残基	Chothia^b	SEQ ID^c	原子	距离
GluGluGluAsnGIyProHisHisLysLysArgArg	49I49I49I53I69I72I73I73I74I74I86I86I	OE1OE2OE2OD1OOND1NE2NZNZNH1NH2	AsnTyrTyrLysSerTyrAspSerAsnAsnTyrTyr	30AL98H99H30DL53H98H94L50H30AL92L30BL30BL	31L101H102H34L53H101H98L50H31L96L32L32L	ND2OHOHNZNNOD1OGOD1OD1OHOH	2.87_2.692.542.742.913.102.872.752.952.613.162.93	残基	原子	残基	Chothia^b	SEQ ID^c	原子	距离

^a跟据IL-13加工形式(SEQ ID NO：4)对氨基酸残基编号。“I”表示IL-13氨基酸。

^b氨基酸残基对应于SEQ ID NO：1(轻链残基，“L”)或SEQ ID NO：2(重链残基，“H”)，且依据Chothia编号系统(Al-Lazikani等人，Jour.Mol.Biol. 273：927-948，1997)编号。

^c氨基酸残基依据SEQ ID NO：1(轻链残基，“L”)或SEQ ID NO：2(重链残基，“H”)的编号而编号。

表4.IL-13与Fab 13.2间的范德瓦尔斯相互作用

IL-13		Fab 13.2
IL-13		Fab 13.2				残基^a	残基	Chothia^b	SEQ ID^c	CDR
SerThrAlaAlaGluGluLeuGluGluGluIleIleIIeIleIleIleAsnAsnAsnArgArgMetSerSerGly	7I8I9I9I12I12I48I49I49I49I52I52I52I52I52I52I53I53I53I65I65I66I68I68I69I	IleIleIleSerIleSerTyrTyrAsnTyrTyrTyrTyrArgTyrLysLysLysLysPheAspSerAspPheSer	30H30H30H53H30H31H98H98H30AL99H99H99H99H50L99H30DL30DL30DL30DL100H96H31H96H100H31H	30H30H30H53H30H31H101H101H31L102H102H102H102H54L102H34L34L34L34L103H99H31H99H103H31H	CDR-H1CDR-H1CDR-H1CDR-H2CDR-H1CDR-H1CDR-H3CDR-H3CDR-L1CDR-H3CDR-H3CDR-H3CDR-H3CDR-L2CDR-H3CDR-L1CDR-L1CDR-L1CDR-L1CDR-H3CDR-H3CDR-H1CDR-H3CDR-H3CDR-H1	残基^a	残基	Chothia^b	SEQ ID^c	CDR

GlyGlyGlyPhePheCysProProProProProProProHisHisHisHisHisHisHisLysLysLysArg

69I69I69I70I70I71I72I72I72I72I72I72I72I73I73I73I73I73I73I73I74I74I74I86I

AlaSerSerSerSerTyrAlaLeuSerTyrTyrGlyTrpAspTrpTrpLeuTyrSerTyrTyrAsnAsnTyr

33H53H52H53H52H98H33H95H52H58H98H97H96L94L96L47H95H58H50H98H98H30AL92L30BL

33H53H52H53H52H101H33H98H52H58H101H100H100L98L100L47H98H58H50H101H101H31L96L32L

CDR-H1CDR-H2CDR-H2CDR-H2CDR-H2CDR-H3CDR-H1CDR-H3CDR-H2CDR-H2CDR-H3CDR-H3CDR-L3CDR-L3CDR-L3CDR-H3CDR-H2CDR-H2CDR-H3CDR-H3CDR-L1CDR-L3CDR-L1

^b氨基酸残基对应于SEQ ID NO：1(轻链残基，“L”)或SEQ ID NO：2(重链残基，“H”)，且依据Chothia编号系统(Al-Lazikani等人，Jour.Mol.Biol. 273：927-948，1997)编号。见表6和7。

表5.由于电子密度不足而误建模的残基

坐标	蛋白质^a	Chothia^b	SEQ ID^c	序列^c	建模为
坐标	蛋白质^a	Chothia^b	SEQ ID^c	序列^c	建模为	Table 11Table 11Table 11Table 11Table 11Table 11Table 11Table 11Table 11Table 11Table 11Table 11	LCHCHCHCHCHCIIIIII	453105171177205	493110176182210899497105108109	LysLysGlnGluLeuLysLysGlnLysLysArgGlu	AlaAlaAlaAlaAlaAlaAlaAlaAlaAlaAlaAla

^a“HC”为重链(SEQ ID NO：2)；“LC”为轻链(SEQ ID NO：1)；“I”为加工后的IL-13(SEQ ID NO：4)。

^c氨基酸残基依据SEQ ID NO：1(轻链残基，“L”)、SEQ ID NO：2(重链残基，“H”)或SEQ ID NO：4(加工后IL-13多肽残基，“I”)的编号而编号。

图3为图示mAb13.2 Fab与人IL-13共结晶结构的带状图。mAb13.2Fab的轻链以深色阴影表示，而重链则以浅色阴影表示。IL-13的结构如右所示。该图描述了IL-13的Cα螺旋与抗体CDR环间的相互作用。与IL-13形成氢键结合的主要mAb13.2重链残基为SER50(CDR2)、SER53(CDR2)、TYR101(CDR3)以及TYR102(CDR3)。与IL-13形成范德瓦尔斯作用的主要mAb13.2重链残基为ILE30(CDR1)、SER31(CDR1)、ALA33(CDR1)、TRP47、SER50(CDR2)、SER52(CDR2)、SER53(CDR2)、TYR58(CDR2)、LEU98(CDR3)、ASP99(CDR3)、GLY100(CDR3)、TYR101(CDR3)、TYR102(CDR3)以及PHE103(CDR3)(见表4；氨基酸编号依据SEQ ID NO：2(图1B)的编号)。

根据SEQ ID NO：1(图1A)的氨基酸编号，与IL-13形成氢键结合的主要mAb13.2轻链残基为ASN31(CDR1)、TYR32(CDR1)、LYS34(CDR1)、ASN96(CDR3)以及ASP98(CDR3)。与IL-13形成范德瓦尔斯作用的主要mAb13.2轻链残基为ASN31(CDR1)、TYR32(CDR1)、LYS34(CDR1)、ARG54(CDR2)、ASN96(CDR3)、ASP98(CDR3)以及TRP100(CDR3)(见表4)。

演化了多种编号体系描述抗体重链和轻链多肽的氨基酸残基。Kabat和Chothia体系编号多肽一定CDR区域中线性接纳的氨基酸残基，其中标明了插入。Kabat系统(Kabat等人，NIH Publ.No.91-3242，第5版，1-3卷，Dept.of Health and Human Services，1991)通过序列可变性定义重链和轻链CDR的位置，而Chothia系统(Al-Lazikani等人，Jour.Mol.Biol.273：927-948，1997)通过环形区域在结构方面定义位置。由于CDR插入的不同位置，这两个系统间重链和轻链氨基酸的编号可能有所差异。氨基酸插入的注解导致这两种编号系统均偏离了线性编号。表6和7根据这三种不同的编号体系，分别比对了mAb13.2 Fab轻链和重链的氨基酸序列(Kabat、Chothia以及线性编号)。

表6.根据线性(SEQ ID NO：1)、Chothia及Kabat编号系统的mAb13.2Fab轻链氨基酸序列。^a

残基	线性序列编号	Chothia结构编号	Kabat序列编号
残基	线性序列编号	Chothia结构编号	Kabat序列编号	DIVLTQSPASLAVSLGQRATISCKASESVDNYGK	12345678910111213141516171819202122232425262728293031323334	12345678910111213141516171819202122232425262728293030A30B30C30D	12345678910111213141516171819202122232425262727A27B27C27D282930

SLMHWYQQKPGQSPKLLIYRASNLESGIPARFSGSGSRT

353637383940414243444546474849505152535455565758596061626364656667686970717273

313233343536373839404142434445464748495051525354555657585960616263646566676869

DFTLTINPVEADDVATYYCQQSNEDPWTFGGGTKLEIKR

7475767778798081828384858687888990919293949596979899100101102103104105106107108109110111112

707172737475767778798081828384858687888990919293949596979899100101102103104105106107108

ADAAPTVSIFPPSSEQLTSGGASVVCFLNNFYPKDINVK

113114115116117118119120121122123124125126127128129130131132133134135136137138139140141142143144145146147148149150151

109110111112113114115116117118119120121122123124125126127128129130131132133134135136137138139140141142143144145146147

WKIDGSERQNGVLNSWTDQDSKDSTYSMSSTLTLTKDEY

152153154155156157158159160161162163164165166167168169170171172173174175176177178179180181182183184185186187188189190

148149150151152153154155156157158159160161162163164165166167168169170171172173174175176177178179180181182183184185186

ERHNSYTCEATHKTSTSPIVKSFNRNEC

191192193194195196197198199200201202203204205206207208209210211212213214215216217218

187188189190191192193194195196197198199200201202203204205206207208209210211212213214

^a黑体字表示Chothia或Kabat编号系统中线性序列的插入。黑体下划线残基表示X射线数据证实的插入。

表7.根据线性(SEQ ID NO：2)、Chothia及Kabat编号系统的mAb13.2Fab重链氨基酸序列。^a

残基	线性序列编号	Chothia结构编号	Kabat序列编号
残基	线性序列编号	Chothia结构编号	Kabat序列编号	EVKLVESGGGLVKPGGSLKLSCAASGFTFISYAM	12345678910111213141516171819202122232425262728293031323334	12345678910111213141516171819202122232425262728293031323334	12345678910111213141516171819202122232425262728293031323334

SWVRQTPEKRLEWVASISSGGNTYYPDSVKGRFTISRDN

353637383940414243444546474849505152535455565758596061626364656667686970717273

ARNILYLQMSSLRSEDTAMYYCARLDGYYFGFAYWGQGT

74757677787980818282A82B82C8384858687888990919293949596979899100100A100B101102103104105106107

LVAVSAAKTTPPSVYPLAPGSAAQTNSMVTLGCLVKGYF

108109110111112113114115116117118119120121122123124125126127128129130131132133134135136137138139140141142143144145146

PEPVTVTWNSGSLSSGVHTFPAVLESDLYTLSSSVTVPS

147148149150151152153154155156157158159160161162163164165166167168169170171172173174175176177178179180181182183184185

SPRPSETVTCNVAHPASSTKVDKKI

191192193194195196197198199200201202203204205206207208209210211212213214215

186187188189190191192193194195196197198199200201202203204205206207208209210

实施例6.白介素13、IL-13受体α1与抑制性抗体mAb13.2 Fab结合结构域的三聚复合物晶体结构

表达C末端融合有6×His标记的IL-13Rα1胞外结构域(残基27-342；见图14)(Aman等人，J.Biol.Chem. 271：29265-29270，1996)。表达在巴斯德毕赤酵母中进行。利用亲和层析在NiNTA-琼脂糖(Qiagen)上纯化重组蛋白质至均质，然后于HiTrap Q Sepharose HP(Pharmacia，AmershamPharmacia Biotech，UK)上实施阴离子交换层析、Superdex-75(Pharmacia)上进行凝胶过滤层析。

如实施例5所述表达并纯化人IL-13(氨基酸残基1至113)(SEQ IDNO：4)。

将受体与稍过量的IL-13混合，形成含有IL-13和IL-13Rα1的复合物。利用分析性大小排阻层析确认复合物的形成后，于37℃用内切糖苷酶Hf(endoHf)(25,000单位/mL)处理复合物90分钟。将去糖基复合物铺于伴刀豆球蛋白A(conA)琼脂糖柱上，以除去带有未裂解寡糖的蛋白质，并将剩下的复合物铺于NiNTA柱上除去EndoHf。通过Superdex-200(GEHealthcare，formerly Amersham Biosciences，Piscatway，NJ)上的凝胶过滤层析，将纯化复合物纯化为均质。在晶体筛选前，利用天然聚丙烯酰胺凝胶电泳及大小寸排阻层析确认形成了IL-13和IL-13Rα1的1∶1复合物。

如实施例4所述纯化mAb13.2 Fab。

于18℃通过悬滴蒸汽扩散使IL-13、IL-13Rα1和mAb13.2 Fab复合物晶体生长，所述悬滴中含有10mg/ml蛋白质复合物、13％PEG-MME2000以及100mM HEPES(pH 7.0)。数周内出现晶体，但直至数月才达到最大。晶体对称空间群为I4，晶胞大小为a＝164.9_，b＝164.9_以及c＝74.8_。在采集数据前，将晶体暂时转移到10％乙二醇加母液中，并在液氮中迅速冷却。在整个数据采集过程中，将晶体维持于100K。于先进光源Berkeley，California的5.0.1光束下采集数据。利用DENZO(Otwinowski和Minor，Methods Enzymol.276：307-326，1997)以及SCALA(“CCP4，”Acta Cryst D50：760-763，1994)整合并精修强度。

利用mAb13.2 Fab/IL-13复合物的坐标(表11)、通过分子置换求解其结构。利用如CCP4(“CCP4，”Acta Cryst D50：760-763，1994)中使用的Solomon，通过母液平滑改进初始相位。利用CCP4中的刚体精修获取初始模型。得到具有连续密度的试验图，利用QUANTA(Accelrys，Inc.，SanDiego，CA)构建初始模型，并用CNS(Brunger等人，Acta Cryst.D54：905-921，1998)针对30至2.2_的数据进行精修。最终的精修模型[包括IL-13Rα1(残基6-314)、mAb13.2 Fab(轻链残基1-213及重链残基1-213)和IL-13(残基6-112)的多肽链，以及123个水分子]工作R值为24.4％，而自由R值为27.2％。数据采集及精修的统计数据见表8和表9。在Ramachandran图的允许区域以外无主链扭转角。利用PYMOL(DeLano，“The PYMOL Molecular Graphics System”(2002)DeLano Scientific，SanCarlos，CA)和Ribbons(Carson，j.AppL.Cryst. 24：958-961，1991)产生结构数据。表12提供了结构坐标。以下IL-13Rα1残基除了C-β原子外不具密度，故截断其各自坐标以示该不确定性：81E、93R、104T、105N、111S、112I、122E、124D、150R、151T、157N、165R、168E、169K、174E、195S、196S、197F、305D、306T、339K、110P、200Q、203Q、204I、209N、212K、213I、214K、240N、279E、284N以及293N。

表8.数据采集及相位确定的统计数据

数据采集	IL-13/mAb13.2Fab/IL-13Rα1
数据采集	IL-13/mAb13.2Fab/IL-13Rα1	晶体系统	四方
空间群	I4	晶体系统	四方
空间群	I4	晶胞大小	a＝b＝164.9_，c＝74.8_，α＝β＝γ＝90.0°
采集数据温度	100K	晶胞大小	a＝b＝164.9_，c＝74.8_，α＝β＝γ＝90.0°
采集数据温度	100K	晶体数	1
放射源	ALS，Berkeley，CA	晶体数	1
放射源	ALS，Berkeley，CA	波长(_)	λ＝1.0_
分辨率范围(_)	30-2.2_	波长(_)	λ＝1.0_
分辨率范围(_)	30-2.2_	最大分辨率(_)	2.2_
R_merge ^a(％)	1.6.7％(48.6％)	最大分辨率(_)	2.2_
R_merge ^a(％)	1.6.7％(48.6％)	完成％	99.9％(99.0％)
总反射(自由)	42298(2110)	完成％	99.9％(99.0％)
总反射(自由)	42298(2110)	唯一反射	40188
I/σ(I)	26.6(2.8)	唯一反射	40188

^aR_merge＝∑|I_h-<I_h>|/∑I_h，其中<I_h>为对称等效的平均强度。

括号内的数字反映了最后一个分辨率壳层的统计数据(2.8_-2.7_)。

表9.结构精修统计数据

数据采集	IL-13/mAb13.2 Fab/IL-13Rα1
数据采集	IL-13/mAb13.2 Fab/IL-13Rα1	分子置换模型	mAb13.2 Fab/IL-13
最大分辨率(_)	2.2_	分子置换模型	mAb13.2 Fab/IL-13
最大分辨率(_)	2.2_	R_work ^a(％)	24.4％
R_free(％)	27.2％	R_work ^a(％)	24.4％

^aR_work＝∑||F_obs|-|F_calc||/∑|F_obs|，R_free与R_work等效，但是从精修过程省略的反射中随机选择6.4％计算得到。

在IL-13和IL-13Rα1间有两处广泛的相互作用。一处是在Ig结构域1和细胞因子中连接螺旋C和D的环的部分之间，而另一处相互作用在受体的Ig结构域3以及IL-13的螺旋A和D之间(见图15)。

IL-13Rα1 Ig结构域1与IL-13的相互作用使得在两个分子间形成了延长的β片层。IL-13(SEQ ID NO：4)中的残基Thr88、Lys89、Ile90和Glu91形成了β链，与受体(SEQ ID NO：12)的残基Lys76、Lys77、Ile78和Ala79相互作用(见图16)。此外，IL-13中Met33的侧链延伸至由这些邻近侧链组成的疏水口袋中。

与Ig结构域3的相互作用的主要特征是将IL-13的一个疏水残基(Phe107)插入受体IL-13Rα1 Ig结构域3的疏水口袋中。IL-13Rα1的疏水口袋是由残基Leu319、Cys257、Arg256和Cys320的侧链组成(图17)。与IL-13的Phe107的相互作用导致了IL-13Rα1(SEQ ID NO：12)的氨基酸残基Ile254、Ser255、Arg256、Lys318、Cys320及Tyr321与IL-13(SEQID NO：4)的氨基酸残基Arg11、Glu12、Leu13、Ile14、Glu15、Lys104、Lys105、Leu106、Phe107和Arg108间的一系列广泛范德瓦尔斯作用(见图17)。

表10.mAb13.2 Fab的结构坐标^a，b

	#	名称	残基链	残基#	X	Y	Z	occ	B	SegID	Ele
	#	名称	残基链	残基#	X	Y	Z	occ	B	SegID	Ele	原子原子原子原子原子原子原子原子原子原子原子原子原子原子原子原子原子原子原子原子原子原子原子原子原子原子原子原子原子原子原子原子原子原子原子原子原子原子原子原子原子	1234567891011121314151617181920212223242526272829303132333435363738394041	NCACOCBCGOD1OD2NCACOCBCG1CG2CD1NCACOCBCG1CG2NCACOCBCGCD1CD2NCACOCBOG1CG2NCAC	ASP LASP LASP LASP LASP LASP LASP LASP LILE LILE LILE LILE LILE LILE LILE LILE LVAL LVAL LVAL LVAL LVAL LVAL LVAL LLEU LLEU LLEU LLEU LLEU LLEU LLEU LLEU LTHR LTHR LTHR LTHR LTHR LTHR LTHR LGLN LGLN LGLN L	11111111222222223333333444444445555555666	5.8495.7587.0718.1155.4136.6207.6236.5476.9818.1718.9008.3557.7407.3958.8957.18310.17010.96511.65212.51212.01612.81011.34211.34112.02712.99112.61511.0369.7639.00710.09414.23415.23315.75116.43316.39715.89617.43015.42915.92517.355	-2.062-0.6200.081-0.534-0.362-0.695-1.136-0.5091.4152.1812.6953.4113.3602.8724.3714.0272.2682.7134.0524.1661.6422.0220.3024.9986.2776.2505.8947.4127.3488.6407.1646.6306.6398.0508.5955.7304.4115.6888.66410.0159.954	0.1820.3810.023-0.1511.8492.7152.1543.927-0.125-0.4760.7671.598-1.351-2.761-1.472-3.7410.8992.0371.7520.8882.3333.5822.5592.6282.6503.8194.9362.8572.0312.2450.5623.5674.6224.8293.9624.2433.9955.3475.9596.1796.681	1.001.001.001.001.001.001.001.001.001.001.001.001.001.001.001.001.001.001.001.001.001.001.001.001.001.001.001.001.001.001.001.001.001.001.001.001.001.001.001.001.00	66.6765.8658.9157.7570.4775.6180.7187.4952.1040.0842.0248.6342.3638.5236.8531.9043.8741.5039.1045.8942.0544.4239.6740.8239.9640.0441.7438.5238.6650.6446.2638.9441.8946.1453.4339.7853.9141.5843.4344.6246.70	LLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLL	NCCOCCOONCCOCCCCNCCOCCCNCCOCCCCNCCOCOCNCC

原子原子原子原子原子原子原子原子原子原子原子原子原子原子原子原子原子原子原子原子原子原子原子原子原子原子原子原子原子原子原子原子原子原子原子原子原子原子原子原子原子原子原子原子原子

424344454647484950515253545556575859606162636465666768697071727374757677787980818283848586

OCBCGCDOE1NE2NCACOCBOGNCACOCBCGCDNCACOCBNCACOCBOGNCACOCBCGCD1CD2NCACOCBNCA

GLN LGLN LGLN LGLN LGLN LGLN LSER LSER LSER LSER LSER LSER LPRO LPRO LPRO LPRO LPRO LPRO LPRO LALA LALA LALA LALA LALA LSER LSER LSER LSER LSER LSER LLEU LLEU LLEU LLEU LLEU LLEU LLEU LLEU LALA LALA LALA LALA LALA LVAL LVAL L

666666777777888888899999101010101010111111111111111112121212121313

17.75815.05213.59612.79611.60613.44118.11719.51119.82319.51720.39921.71220.42620.79919.60718.45221.88321.35820.91119.90518.88318.72817.61919.28919.85619.88520.66021.47820.56219.86320.42821.09421.19920.20620.24520.73522.00519.66922.39422.79823.24724.32223.94622.35722.652

8.98910.78010.84911.85811.67912.92910.99311.09112.56813.35810.48310.25412.96012.05711.77711.96512.83814.21914.32311.34111.03312.22112.5649.82412.84114.00615.10314.84013.67312.64716.33517.44918.55818.91417.91919.03118.57219.34619.11020.15921.41821.48519.62022.42823.673

7.3267.1796.7647.5537.7627.9796.3646.7636.9126.0335.6766.1528.0379.12010.0289.6409.8419.7608.31711.24412.21513.13613.53912.99313.47114.34513.65612.78615.66316.32314.06913.44114.46815.09912.27011.36810.67110.34514.64315.57514.83214.25116.42914.83114.132

1.001.001.001.001.001.001.001.001.001.001.001.001.001.001.001.001.001.001.001.001.001.001.001.001.001.001.001.001.001.001.001.001.001.001.001.001.001.001.001.001.001.001.001.001.00

45.0844.4137.3127.0441.6938.9449.5549.1644.3848.0451.8968.3144.4747.0650.0056.5644.6039.0244.3242.7630.8434.0234.1036.3133.7334.2130.6137.1939.8558.4329.1829.4434.4538.4938.7834.3854.9044.6339.6336.4635.2440.4739.4033.9444.79

LLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLL

OCCCONNCCOCONCCOCCCNCCOCNCCOCONCCOCCCCNCCOCNC

87888990919293949596979899100101102103104105106107108109110111112113114115116117118119120121122123124125126127128129130131

COCBCG1CG2NCACOCBOGNCACOCBCGCD1CD2NCACONCACOCBCGCDOE1NE2NCACOCBCGCDNECZNH1NH2NCA

VAL LVAL LVAL LVAL LVAL LSER LSER LSER LSER LSER LSER LLEU LLEU LLEU LLEU LLEU LLEU LLEU LLEU LGLY LGLY LGLY LGLY LGLN LGLN LGLN LGLN LGLN LGLN LGLN LGLN LGLN LARG LARG LARG LARG LARG LARG LARG LARG LARG LARG LARG LALA LALA L

131313131314141414141415151515151515151616161617171717171717171718181818181818181818181919

22.48521.74721.69821.87721.97723.24223.14522.21922.09124.54925.51421.52720.60021.16422.35020.32519.47019.07918.16220.30820.76321.51021.80221.82622.53721.54520.36123.41724.39725.31425.59425.79322.03421.17921.28122.35021.58620.98921.45022.90923.56922.90924.89820.14820.080

24.88924.87923.78725.14322.68025.95327.17728.19628.26927.76526.79128.97629.97130.66930.95330.99830.42531.48429.81031.01731.75730.95531.47329.70228.87228.15828.47127.85128.48029.47830.55629.12527.19726.44224.96924.46426.67825.70126.04126.05426.45726.89126.41524.28722.869

15.04716.02312.94212.25811.94214.71915.50514.83913.62415.65015.24615.68815.16013.91813.81616.26117.39418.42816.89612.96711.80710.7649.68311.06810.1119.2159.22010.83311.79811.11711.6589.9278.4407.5437.8648.1866.0945.1053.7063.5752.4881.4192.4657.7878.054

43.0342.0742.4442.2556.6646.4950.9946.5151.5251.1860.8141.4743.6643.1250.8945.4539.7450.2848.8239.3437.8336.3245.2830.6133.7632.6533.3034.7550.0550.9848.4532.8834.5029.7533.9240.9632.7527.8137.2356.9552.8648.4246.6634.8931.86

LLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLL

COCCCNCCOCONCCOCCCCNCCONCCOCCCONNCCOCCCNCNNNC

132133134135136137138139140141142143144145146147148149150151152153154155156157158159160161162163164165166167168169170171172173174175176

COCBNCACOCBOG1CG2NCACOCBCG1CG2CD1NCACOCBOGNCACOCBSGNCACOCBCGCDCENZNCACOCBN

ALA LALA LALA LTHR LTHR LTHR LTHR LTHR LTHR LTHR LILE LILE LILE LILE LILE LILE LILE LILE LSER LSER LSER LSER LSER LSER LCYS LCYS LCYS LCYS LCYS LCYS LLYS LLYS LLYS LLYS LLYS LLYS LLYS LLYS LLYS LALA LALA LALA LALA LALA LSER L

191919202020202020202121212121212121222222222222232323232323242424242424242424252525252526

19.52518.62119.15620.07419.57719.26920.07020.59520.87520.02118.09017.70017.58217.23616.34816.52115.88615.32017.88517.83416.85616.62919.23519.18516.27815.32715.56815.55213.88112.48015.83816.02914.97714.76517.43118.48918.57119.88921.08914.30813.27513.77514.53412.04913.334

22.23422.78122.60521.09320.41018.97918.31320.40221.74519.67218.51217.15116.40716.98917.10317.74715.65317.55015.11514.25713.11412.68513.70312.60412.64711.53810.76311.32812.06610.8819.4738.6467.5486.8588.0408.95410.29311.00410.2927.4096.4075.2215.3797.0234.034

6.7996.1859.2226.4055.2285.6026.2374.0633.6572.8745.2225.5164.1953.1576.2917.6666.4838.5824.2513.0833.2904.4192.7831.8862.1842.1770.892-0.1982.2012.1341.021-0.154-0.1630.839-0.184-0.787-0.064-0.3560.216-1.298-1.455-2.274-3.224-2.121-1.886

32.5937.7826.1336.2741.5444.5558.6539.5350.9237.4745.4238.4438.2839.7443.1144.2247.7356.6733.3332.4727.0732.1730.9638.4219.5132.0733.6834.6134.2042.4932.6335.4738.0941.4539.2058.6973.7282.4965.3834.0536.5237.0640.6732.0936.30

LLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLL

COCNCCOCOCNCCOCCCCNCCOCONCCOCSNCCOCCCCNNCCOCN

177178179180181182183184185186187188189190191192193194195196197198199200201202203204205206207208209210211212213214215216217218219220221

CACOCBOGNCACOCBCGCDOE1OE2NCACOCBOGNCACOCBCG1CG2NCACOCBCGOD1OD2NCACOCBCGOD1ND2NCA

SER LSER LSER LSER LSER LGLU LGLU LGLU LGLU LGLU LGLU LGLU LGLU LGLU LSER LSER LSER LSER LSER LSER LVAL LVAL LVAL LVAL LVAL LVAL LVAL LASP LASP LASP LASP LASP LASP LASP LASP LASN LASN LASN LASN LASN LASN LASN LASN LTYR LTYR L

262626262627272727272727272728282828282829292929292929303030303030303030A30A30A30A30A30A30A30A30B30B

13.69813.13013.62513.16511.74912.08811.44911.02910.71210.21510.5139.2538.9528.55611.01610.6599.2348.28810.78410.8149.1617.8757.3026.5368.0808.9598.7437.7257.3146.0505.8958.4669.3689.8069.6135.1073.8803.7393.1512.6841.4250.7161.1724.3404.180

2.8042.7281.9691.6301.6703.5083.5104.9155.7372.6021.1120.263-0.2140.0705.1846.5276.9016.1446.5787.9408.0988.6439.64510.5419.3398.47910.6879.49010.48210.0528.91410.67411.79412.59011.86411.00710.70111.54612.61910.94910.50311.2879.18511.03811.735

-2.556-3.973-4.798-1.756-1.717-4.248-5.562-5.964-5.113-5.549-5.429-5.329-4.217-6.354-7.266-7.708-7.290-7.465-9.232-9.657-6.720-6.291-7.303-6.971-4.945-4.041-5.153-8.572-9.561-10.314-10.735-10.547-10.050-10.882-8.849-10.446-11.174-12.440-12.450-10.255-10.956-11.583-10.878-13.532-14.806

39.6744.7251.0045.8646.3742.9336.1935.8944.1533.0338.9234.1456.0049.0442.5744.7649.6245.1645.0443.9051.2648.3549.0353.8145.0945.7339.0150.4951.8955.2256.8158.5771.0385.5370.1662.3166.2172.1971.9171.8977.1879.2382.3979.0984.64

LLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLL

CCOCONCCOCCCOONCCOCONCCOCCCNCCOCCOONCCOCCONNC

222223224225226227228229230231232233234235236237238239240241242243244245246247248249250251252253254255256257258259260261262263264265266

COCBCGCD1CD2CE1CE2CZOHNCACONCACOCBCGCDCENZNCACOCBOGNCACOCBCGCD1CD2NCACOCBCGSDCE

TYR LTYR LTYR LTYR LTYR LTYR LTYR LTYR LTYR LTYR LGLY LGLY LGLY LGLY LLYS LLYS LLYS LLYS LLYS LLYS LLYS LLYS LLYS LSER LSER LSER LSER LSER LSER LLEU LLEU LLEU LLEU LLEU LLEU LLEU LLEU LMET LMET LMET LMET LMET LMET LMET LMET L

30B30B30B30B30B30B30B30B30B30B30C30C30C30C30D30D30D30D30D30D30D30D30D31313131313132323232323232323333333333333333

4.8794.4032.6842.0491.9601.5301.3490.9280.8390.2246.0156.7906.8237.5335.9915.9206.2545.8404.5094.2093.2113.0662.7857.0277.4206.4076.1958.7989.7345.7774.7965.5015.3383.7343.2051.9752.8836.2887.0696.6186.4808.5679.5199.1869.514

13.09914.07011.91710.5959.66910.2778.4429.0468.1306.91013.18214.41915.11916.09314.61915.26314.29513.14315.83116.96017.97819.21218.79414.77713.96114.07515.15614.39114.40812.95612.95012.68911.64511.89512.10311.24113.57413.67513.63114.83715.92113.74113.69912.32410.867

-14.807-15.380-15.066-15.306-14.270-16.562-14.482-16.777-15.744-15.945-14.087-14.111-12.749-12.535-11.818-10.510-9.367-9.350-10.333-11.324-10.767-11.664-13.035-8.402-7.261-6.127-5.571-6.760-7.818-5.788-4.717-3.393-2.772-5.002-6.424-6.665-6.625-2.982-1.756-0.949-1.503-2.109-0.9370.219-0.802

1.001.001.001.001.001.001.001.001.001.001.001.001.001.001.001.001.001.001.001.001.001.001.0011.001.001.001.001.001.001.001.001.001.001.001.001.001.001.001.001.001.001.001.001.001.00

80.8978.2192.55106.94124.67117.46130.56130.84132.90133.3077.3976.4975.1177.1467.8758.9154.1853.3959.2663.9882.6798.6008.4248.7048.6446.4646.1344.7648.1540.4736.9638.5740.4137.9438.0940.0818.3039.4235.6936.1739.2635.2529.0463.7861.41

LLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLL

COCCCCCCCONCCONCCOCCCCNNCCOCONCCOCCCCNCCOCCSC

267268269270271272273274275276277278279280281282283284285286287288289290291292293294295296297298299300301302303304305306307308309310311

NCACOCBCGND1CD2CE1NE2NCACOCBCGCD1CD2NE1CE2CE3CZ2CZ3CH2NCACOCBCGCD1CD2CE1CE2CZOHNCACOCBCGCDOE1NE2

HIS LHIS LHIS LHIS LHIS LHIS LHIS LHIS LHIS LHIS LTRP LTRP LTRP LTRP LTRP LTRP LTRP LTRP LTRP LTRP LTRP LTRP LTRP LTRP LTYR LTYR LTYR LTYR LTYR LTYR LTYR LTYR LTYR LTYR LTYR LTYR LGLN LGLN LGLN LGLN LGLN LGLN LGLN LGLN LGLN L

343434343434343434343535353535353535353535353535363636363636363636363636373737373737373737

6.3835.9306.6897.0114.4263.5883.3972.8822.6092.2826.9587.6656.8266.0308.8779.95310.08511.06411.21111.83311.48313.00412.64813.3917.0236.2997.2188.3595.3384.3494.7033.0603.8002.1462.5161.5876.7037.4196.5405.3357.6718.1558.1777.1549.340

14.65915.77315.79914.74715.64915.26116.08714.13715.48914.30416.99217.11017.61518.54818.02317.47517.62916.67616.98116.38616.17615.61315.40615.13417.00617.43317.80917.35516.35315.95815.07216.47014.70616.11215.23014.85218.67419.13118.82519.04220.63321.19422.70723.34923.285

0.3471.1812.5063.0521.4850.307-0.7800.051-1.654-1.1733.0304.2995.4875.3674.1453.2931.9543.7221.5132.5794.9602.6335.0103.8566.6507.8238.9689.0548.2817.2226.2067.2305.2336.2625.2694.3319.83211.00312.19812.16910.95012.28112.30612.08812.581

32.5530.9632.2737.9631.5113.7126.3618.4216.7628.7730.3528.1330.8631.7425.5033.5422.1541.0539.9339.8337.3234.8939.5325.2326.9324.5627.7329.4127.1328.8432.7029.1929.5032.0528.9031.1625.7229.4227.2030.3830.1339.2836.6638.8429.96

LLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLL

NCCOCCNCCNNCCOCCCCNCCCCCNCCOCCCCCCCONCCOCCCON

312313314315316317318319320321322323324325326327328329330331332333334335336337338339340341342343344345346347348349350351352353354355356

NCACOCBCGCDOE1NE2NCACOCBCGCDCENZNCACOCBCGCDNCACONCACOCBCGCDOE1NE2NCACOCBOGN

GLN LGLN LGLN LGLN LGLN LGLN LGLN LGLN LGLN LLYS LLYS LLYS LLYS LLYS LLYS LLYS LLYS LLYS LPRO LPRO LPRO LPRO LPRO LPRO LPRO LGLY LGLY LGLY LGLY LGLN LGLN LGLN LGLN LGLN LGLN LGLN LGLN LGLN LSER LSER LSER LSER LSER LSER LPRO L

383838383838383838393939393939393939404040404040404141414142424242424242424243434343434344

7.1456.4057.1948.1936.1525.4375.1135.8803.9746.7377.3637.0195.9376.8487.0646.5106.9136.5007.9387.7326.4006.0558.9399.9839.2225.6484.3673.2232.1053.4832.4292.3012.9752.6742.9083.2143.4303.2341.4201.2111.9302.415-0.280-0.9072.018

18.29017.98218.49017.89816.48116.08214.60413.76014.27719.61420.23219.40318.81021.66022.52723.88724.84126.22619.35118.57518.85920.01118.95019.25720.06217.79017.92918.22018.42418.23518.50917.43916.41019.85820.99722.30323.33022.26717.68916.75717.23018.35916.60917.87216.367

13.24514.43715.62316.02114.54915.83415.89115.41916.48616.16617.32418.54618.63417.49516.27716.51515.41815.76419.51320.73721.42921.72421.58720.56019.55321.66822.32621.38321.83420.08019.11318.03118.05918.44919.41918.71619.35117.38717.07115.97214.71014.63315.69915.66313.702

27.6426.9427.2829.5422.5129.2429.2432.4939.8728.4326.3131.4732.5725.1521.4225.9525.4941.9433.6737.2942.7940.4342.8639.7729.9243.7846.5643.6849.5541.0040.6842.3840.2044.0153.3247.8082.5257.9841.1442.5640.8443.6740.5947.2835.42

LLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLL

NCCOCCCONNCCOCCCCNNCCOCCCNCCONCCOCCCONNCCOCON

357358359360361362363364365366367368369370371372373374375376377378379380381382383384385386387388389390391392393394395396397398399400401

CACOCBCGCDNCACOCBCGCDCENZNCACOCBCGCD1CD2NCACOCBCGCD1CD2NCACOCBCG1CG2CD1NCACOCBCG

PRO LPRO LPRO LPRO LPRO LPRO LLYS LLYS LLYS LLYS LLYS LLYS LLYS LLYS LLYS LLEU LLEU LLEU LLEU LLEU LLEU LLEU LLEU LLEU LLEU LLEU LLEU LLEU LLEU LLEU LLEU LILE LILE LILE LILE LILE LILE LILE LILE LTYR LTYR LTYR LTYR LTYR LTYR L

444444444444454545454545454545464646464646464647474747474747474848484848484848494949494949

2.7052.0940.9232.6232.7041.7342.9122.6613.1364.2783.4382.7123.5742.7363.3282.3872.9053.7153.3251.7452.0622.8430.7504.8485.7215.8905.7017.1007.2898.7386.9236.2746.4795.6645.5837.9818.8968.1128.7315.0474.2604.7065.1552.7522.286

16.79218.02618.32215.55014.44814.92518.74720.00019.89919.55921.09622.44223.58024.70725.12820.25220.25021.51222.60420.15120.04818.75120.06821.35422.48222.62023.69422.26721.94121.53423.13621.51721.49920.34019.32521.22722.34221.05823.66120.49919.42419.32720.31819.69220.901

12.48411.82612.00711.60112.59513.66211.07110.4058.9728.69111.13611.10111.65112.26413.5337.9296.5586.2826.6795.5614.0633.7523.3055.6105.2883.7763.1955.8947.3677.5788.2233.1481.7161.2251.9161.3361.865-0.1731.2160.052-0.568-2.021-2.604-0.488-1.257

36.1033.0641.8934.1733.7033.4837.4132.2536.1443.3736.8730.7563.5373.2286.9838.4731.5627.5630.4130.5132.2033.5023.2028.5328.0428.7029.8125.6527.8738.3732.8328.3427.5126.9723.9530.5816.4030.4027.5826.3628.3731.6427.8426.5528.05

LLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLL

CCOCCCNCCOCCCCNNCCOCCCCNCCOCCCCNCCOCCCCNCCOCC

402403404405406407408409410411412413414415416417418419420421422423424425426427428429430431432433434435436437438439440441442443444445446

CD1CD2CE1CE2CZOHNCACOCBCGCDNECZNH1NH2NCACOCBNCACOCBOGNCACOCBCGOD1ND2NCACOCBCGCD1CD2N

TYR LTYR LTYR LTYR LTYR LTYR LARG LARG LARG LARG LARG LARG LARG LARG LARG LARG LARG LALA LALA LALA LALA LALA LSER LSER LSER LSER LSER LSER LASN LASN LASN LASN LASN LASN LASN LASN LLEU LLEU LLEU LLEU LLEU LLEU LLEU LLEU LGLU L

494949494949505050505050505050505051515151515252525252525353535353535353545454545454545455

1.9962.1341.5701.7111.4291.0094.5864.9966.4526.7854.0753.8692.5702.6211.6350.5081.7777.3168.7359.22510.2309.2648.5609.0848.1378.52710.1069.4796.9065.9445.7915.6204.6024.5964.4084.8135.8395.6504.1693.3386.2536.1957.1256.5953.840

20.82422.12721.92123.22523.12124.24418.12117.80718.21018.94318.48917.65418.00719.30920.20219.94821.35717.73518.01919.45219.62117.56620.48321.82123.00624.13922.16722.32222.76023.83824.22923.36223.39523.25524.23322.04025.52525.91625.93926.55527.31027.78926.99129.25625.195

-2.614-0.625-3.308-1.317-2.656-3.339-2.580-3.944-4.163-5.091-4.965-6.233-6.937-7.604-7.586-6.929-8.225-3.278-3.357-3.079-2.383-4.698-3.600-3.346-3.194-3.433-4.422-5.677-2.779-2.609-1.153-0.289-3.140-4.622-5.336-5.110-0.8690.5190.8960.2420.7002.1503.0652.3061.966

26.5031.299.3722.7121.5629.1531.1831.8330.1636.3535.3438.8642.1147.8361.8175.4259.0924.0726.9832.9932.3323.6032.3630.4131.9134.9431.8437.8532.3024.5028.2837.5313.3119.6139.4218.5323.5919.7331.2334.4611.4610.4123.5920.8232.72

LLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLL

CCCCCONCCOCCCNCNNNCCOCNCCOCONCCOCCONNCCOCCCCN

447448449450451452453454455456457458459460461462463464465466467468469470471472473474475476477478479480481482483484485486487488489490491

CACOCBCGCDOE1OE2NCACOCBOGNCACONCACOCBCG1CG2CD1NCACOCBCGCDNCACOCBNCACOCBCGCD

GLU LGLU LGLU LGLU LGLU LGLU LGLU LGLU LSER LSER LSER LSER LSER LSER LGLY LGLY LGLY LGLY LILE LILE LILE LILE LILE LILE LILE LILE LPRO LPRO LPRO LPRO LPRO LPRO LPRO LALA LALA LALA LALA LALA LARG LARG LARG LARG LARG LARG LARG L

555555555555555556565656565657575757585858585858585859595959595959606060606061616161616161

2.4502.0422.8602.2890.883-0.0960.148-1.0800.7280.2590.4320.403-1.214-1.4530.5760.6902.0562.2802.9814.3125.2905.2414.7613.8096.1913.7856.1977.2148.0008.2578.1077.2216.4368.3939.13810.60911.4708.98710.89212.27012.39713.15212.77411.81912.451

25.23126.63627.48224.27324.31023.78323.94923.16826.88528.16828.26227.27028.30727.63729.46429.61729.25629.32228.86728.50729.58430.06427.15126.05126.81725.88629.97431.00730.70029.53030.92730.34629.30431.73631.49331.22831.85232.65530.31429.94128.42827.84830.56330.55231.161

2.3792.8083.1373.5554.1483.1301.9453.5332.7523.2464.7585.4752.8751.6365.2986.7337.2808.4876.4116.8696.4525.3276.2806.7456.7488.2387.3617.1145.8355.5258.3539.3948.6495.0953.8684.1413.5462.8955.0655.3505.3556.1276.6647.8069.057

36.5444.6250.4733.9841.0241.6554.5161.0948.7541.1639.7247.9440.0157.1937.3938.1037.9048.9941.8833.2936.3940.9533.8122.6728.5723.5435.7437.6641.0239.7831.3635.7032.2044.3441.5539.4942.7842.7341.3636.6530.3232.0935.3839.4542.92

LLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLL

CCOCCCOONCCOCONCCONCCOCCCCNCCOCCCNCCOCNCCOCCC

492493494495496497498499500501502503504505506507508509510511512513514515516517518519520521522523524525526527528529530531532533534535536

NECZNH1NH2NCACOCBCGCD1CD2CE1CE2CZNCACOCBOGNCACONCACOCBOGNCACONCACOCBOGNCACO

ARG LARG LARG LARG LPHE LPHE LPHE LPHE LPHE LPHE LPHE LPHE LPHE LPHE LPHE LSER LSER LSER LSER LSER LSER LGLY LGLY LGLY LGLY LSER LSER LSER LSER LSER LSER LGLY LGLY LGLY LGLY LSER LSER LSER LSER LSER LSER LARG LARG LARG LARG L

616161616262626262626262626262636363636363646464646565656565656666666667676767676768686868

11.72311.82212.72510.99711.63811.61411.63811.13310.34310.39311.0669.76711.1109.80910.47812.20512.23812.63313.32613.22714.57912.21212.56312.89612.52413.61013.96114.32714.55815.12016.28514.36614.68413.68112.82113.80112.88513.19214.10413.04214.30912.42112.60512.82511.904

30.73029.51228.66829.12727.81026.36526.07226.86025.78425.67224.62326.61724.52626.52225.48324.95324.67623.24722.62925.61725.31622.72421.35721.13421.93520.05019.72818.25617.56120.60120.33917.79816.42115.84716.55014.56313.90012.42012.00014.42314.10511.63610.1839.5699.098

10.24910.77410.31211.7344.4534.2602.7551.9704.8836.3796.9837.1828.3658.5619.1542.3330.9020.6121.4020.1980.539-0.531-0.861-2.328-3.180-2.624-4.000-4.147-3.160-4.487-3.742-5.395-5.690-6.671-7.178-6.954-7.855-7.790-7.076-9.284-9.835-8.531-8.578-7.185-6.533

55.5947.5650.5651.7728.2825.2922.9633.2831.6225.2922.7224.9341.7830.5223.5223.1730.2227.5233.3838.8846.5624.5830.2233.2736.1233.3538.5236.4342.0837.3450.7233.1331.5836.0337.0339.4144.5949.8248.3748.3556.5952.6654.2547.3545.82

LLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLL

NCNNNCCOCCCCCCCNCCOCONCCONCCOCONCCONCCOCONCCO

537538539540541542543544545546547548549550551552553554555556557558559560561562563564565566567568569570571572573574575576577578579580581

CBCGCDNECZNH1NH2NCACOCBOG1CG2NCACOCBCGOD1OD2NCACOCBCGCD1CD2CE1CE2CZNCACOCBOG1CG2NCACOCB

ARG LARG LARG LARG LARG LARG LARG LTHR LTHR LTHR LTHR LTHR LTHR LTHR LASP LASP LASP LASP LASP LASP LASP LASP LPHE LPHE LPHE LPHE LPHE LPHE LPHE LPHE LPHE LPHE LPHE LTHR LTHR LTHR LTHR LTHR LTHR LTHR LLEU LLEU LLEU LLEU LLEU L

686868686868686969696969696970707070707070707171717171717171717171727272727272727373737373

13.80613.38913.85114.58014.44613.68415.09514.06814.34915.11015.19315.09916.29614.21815.67816.41415.68615.22717.82918.75719.97118.29615.59914.99915.71316.45813.52612.83912.65812.36411.99411.69611.51015.49016.10815.27114.69917.49617.35518.33515.17814.47415.45616.31013.509

9.8879.5488.1457.5036.1715.4915.5379.5698.9469.7439.3167.6297.8736.63110.88211.68712.99713.61812.01410.82111.0559.67013.41714.68815.29914.65014.44913.78212.40414.54011.78613.91212.53516.60917.29518.48819.22817.76918.68216.57418.63419.78020.78420.45419.274

-9.475-10.906-11.319-10.223-10.089-10.928-9.107-6.708-5.419-4.364-3.217-5.618-6.375-6.357-4.736-3.767-3.548-4.507-4.258-4.248-4.428-4.073-2.286-1.908-0.7050.018-1.567-2.718-2.703-3.776-3.752-4.823-4.816-0.5320.5911.0410.2490.155-0.936-0.3032.3722.9203.5224.3343.996

61.5672.1289.41103.03112.09118.70113.3139.6240.5840.8939.2446.7258.1245.5844.0644.0942.3841.6952.5558.2372.2056.4331.6528.6728.2833.9825.7332.6128.9522.5443.2833.3923.2823.1030.2628.3837.5525.3651.9141.8731.3630.1028.1330.0837.24

LLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLL

CCCNCNNNCCOCOCNCCOCCOONCCOCCCCCCCNCCOCOCNCCOC

582583584585586587588589590591592593594595596597598599600601602603604605606607608609610611612613614615616617618619620621622623624625626

CGCD1CD2NCACOCBOG1CG2NCACOCBCG1CG2CD1NCACOCBCGOD1ND2NCACOCBCGCDNCACOCBCG1CG2NCACOCB

LEU LLEU LLEU LTHR LTHR LTHR LTHR LTHR LTHR LTHR LILE LILE LILE LILE LILE LILE LILE LILE LASN LASN LASN LASN LASN LASN LASN LASN LPRO LPRO LPRO LPRO LPRO LPRO LPRO LVAL LVAL LVAL LVAL LVAL LVAL LVAL LGLU LGLU LGLU LGLU LGLU L

737373747474747474747575757575757575767676767676767677777777777777787878787878787979797979

13.01011.82612.54015.39516.41815.81614.88817.01617.20618.37116.36415.77516.80717.71315.11215.59615.37014.42416.64617.48916.65215.85018.28219.49719.78920.22516.83317.74617.02415.81318.29417.25216.24417.82817.24916.89217.46718.27617.92318.29215.87415.48215.12014.91014.282

20.39321.15119.88022.05423.01324.17024.82823.58622.55624.26624.36125.43626.52726.34624.81825.43223.30325.87327.63528.81930.08730.46528.89429.76430.24829.96430.74030.27029.42329.23931.52832.63631.99028.87528.09829.00130.05927.05226.53425.89028.56629.37828.51727.31530.235

4.9154.3136.2773.1583.6104.4003.9782.3821.4742.6415.5876.3336.6327.4027.5498.8177.6359.6565.9195.9866.1645.3174.6794.8675.9573.7567.3308.3559.4109.3899.0208.8407.76910.34011.43212.61712.82811.87113.26710.89413.38614.53715.75415.65714.130

24.1521.1625.7034.0229.7731.1443.2329.5942.7110.5434.4541.4541.8343.1744.2744.8349.0734.1640.2435.5839.8646.5836.3339.9040.7038.2238.9742.0941.4446.2643.7234.2340.3138.9432.5137.0339.7528.6919.4029.9738.0227.3434.8938.0616.08

LLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLL

CCCNCCOCOCNCCOCCCCNCCOCCONNCCOCCCNCCOCCCNCCOC

627628629630631632633634635636637638639640641642643644645646647648649650651652653654655656657658659660661662663664665666667668669670671

CGCDOE1OE2NCACOCBNCACOCBCGOD1OD2NCACOCBCGOD1OD2NCACOCBCG1CG2NCACOCBNCACOCBOG1CG2N

GLU LGLU LGLU LGLU LALA LALA LALA LALA LALA LASP LASP LASP LASP LASP LASP LASP LASP LASP LASP LASP LASP LASP LASP LASP LASP LVAL LVAL LVAL LVAL LVAL LVAL LVAL LALA LALA LALA LALA LALA LTHR LTHR LTHR LTHR LTHR LTHR LTHR LTYR L

797979798080808080818181818181818182828282828282828383838383838384848484848585858585858586

14.70213.47413.60412.38815.11514.91213.65013.62614.82312.58811.30311.19410.12610.1968.8248.3988.17312.30512.27312.67012.72813.16512.66211.43213.48812.95213.29312.09710.97813.63714.87712.47112.34811.30311.90313.11710.26511.04211.49210.7989.63011.06511.70311.48311.531

31.56832.41433.47831.99729.19028.48327.61126.50629.53028.13527.45526.37625.82128.50527.89227.13528.17226.06425.04323.66022.69125.45426.70426.85327.53323.56222.26321.34821.65522.31323.16222.85620.22519.27418.09318.00119.94017.17116.04516.29516.68914.68514.51813.54016.094

13.50713.25712.66913.65816.92318.18818.18818.71719.29917.59017.56116.47816.22817.41017.26318.17016.23115.83814.81715.34914.58913.64312.95012.82312.52116.64617.20116.99717.41718.71718.93219.51616.33716.03315.29315.10315.15014.89314.10412.77312.74014.70515.97413.79911.685

50.1565.8880.4778.6739.0134.3339.6852.1528.8838.6640.4736.2241.2342.4357.8369.7268.6030.2228.4329.3027.9431.7431.0545.5850.6428.2233.7228.2920.5534.5157.2838.2427.8919.9925.3925.6822.5434.1537.6836.4936.4336.9743.4718.6129.71

LLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLL

CCOONCCOCNCCOCCOONCCOCCOONCCOCCCNCCOCNCCOCOCN

672673674675676677678679680681682683684685686687688689690691692693694695696697698699700701702703704705706707708709710711712713714715716

CACOCBCGCD1CD2CE1CE2CZOHNCACOCBCGCD1CD2CE1CE2CZOHNCACOCBSGNCACOCBCGCDOE1NE2NCACOCBCGCD

TYR LTYR LTYR LTYR LTYR LTYR LTYR LTYR LTYR LTYR LTYR LTYR LTYR LTYR LTYR LTYR LTYR LTYR LTYR LTYR LTYR LTYR LTYR LCYS LCYS LCYS LCYS LCYS LCYS LGLN LGLN LGLN LGLN LGLN LGLN LGLN LGLN LGLN LGLN LGLN LGLN LGLN LGLN LGLN LGLN L

868686868686868686868687878787878787878787878788888888888889898989898989898990909090909090

11.00110.87911.81411.91711.93112.62711.18312.57411.12611.82311.7729.7219.4959.0978.2998.3708.4428.1228.7558.1088.7428.4188.4119.6469.2438.1057.93810.40711.4757.3026.1925.9205.9874.9613.6952.7792.4552.3495.6475.3643.8723.2466.3526.3915.263

16.32415.01714.22617.30618.67818.90819.72620.13620.95121.15322.37814.78713.55013.74214.61912.71512.44813.44011.18013.16810.90011.89411.61212.90912.95011.92411.04712.62411.17312.05811.15111.10912.12911.65210.81811.31212.49410.4089.9219.7949.4648.9938.8237.4586.565

10.3629.6169.5889.62110.26411.4309.73412.05410.34711.50912.1379.0128.2756.8286.5138.89710.38111.30410.85712.65112.20113.09314.4385.9494.5554.4235.2713.6003.9163.3803.1671.6750.9953.9453.8212.7242.6701.8431.159-0.260-0.3650.575-0.923-0.303-0.773

19.3022.6026.9420.2917.439.9618.4225.7310.3124.9826.2225.8429.2229.4634.4130.1337.4923.5620.6130.2529.1538.7753.0136.9536.0334.8939.8532.8343.4030.6530.5032.4732.8030.5322.5221.9330.3937.8731.9738.1239.8941.1831.7140.3639.74

LLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLL

CCOCCCCCCCONCCOCCCCCCCONCCOCSNCCOCCCONNCCOCCC

717718719720721722723724725726727728729730731732733734735736737738739740741742743744745746747748749750751752753754755756757758759760761

OE1NE2NCACOCBOGNCACOCBCGOD1ND2NCACOCBCGCDOE1OE2NCACOCBCGOD1OD2NCACOCBCGCDNCACOCB

GLN LGLN LSER LSER LSER LSER LSER LSER LASN LASN LASN LASN LASN LASN LASN LASN LGLU LGLU LGLU LGLU LGLU LGLU LGLU LGLU LGLU LASP LASP LASP LASP LASP LASP LASP LASP LPRO LPRO LPRO LPRO LPRO LPRO LPRO LTRP LTRP LTRP LTRP LTRP L

909091919191919192929292929292929393939393939393939494949494949494959595959595959696969696

4.8314.7653.3531.9481.7910.7311.0131.4072.8772.8962.4651.9304.2914.3493.5025.3442.7112.3261.6771.9863.5534.4763.9744.7372.8210.7740.1210.8831.332-1.334-2.158-1.734-3.2291.0470.5531.4742.6890.5321.7641.6910.8981.6922.5722.0850.783

6.6555.7119.7609.4728.9539.04310.68811.7428.3907.8796.4276.0198.0447.6498.0576.8425.6444.2363.9144.5373.3283.6493.1063.1642.6232.9432.5311.3230.4732.1583.3464.0293.5971.2342.2023.4043.2441.3890.5580.0954.6005.8145.6665.4107.032

-1.9210.116-1.570-1.784-3.225-3.842-1.596-2.446-3.735-5.091-5.208-6.234-5.676-7.118-7.911-7.473-4.166-4.167-2.829-1.821-4.338-5.515-6.838-7.832-6.887-2.822-1.588-1.053-1.823-1.856-2.316-3.280-1.7170.2751.2551.3681.3812.5352.3790.9501.4461.5752.7983.8981.716

36.3446.0236.9141.3039.8944.6340.4944.8540.0840.1241.2739.9442.7745.0247.4958.3941.3948.6648.4250.6455.5962.9578.9284.8781.5649.3551.3750.2550.3149.0969.2879.2883.4846.1745.8144.5649.3149.2042.4644.0739.9033.9432.0634.4933.74

LLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLL

ONNCCOCONCCOCCONNCCOCCCOONCCOCCOONCCOCCCNCCOC

762763764765766767768769770771772773774775776777778779780781782783784785786787788789790791792793794795796797798799800801802803804805806

CGCD1CD2NE1CE2CE3CZ2CZ3CH2NCACOCBOG1CG2NCACOCBCGCD1CD2CE1CE2CZNCACONCACONCACONCACOCBOG1

TRP LTRP LTRP LTRP LTRP LTRP LTRP LTRP LTRP LTHR LTHR LTHR LTHR LTHR LTHR LTHR LPHE LPHE LPHE LPHE LPHE LPHE LPHE LPHE LPHE LPHE LPHE LGLY LGLY LGLY LGLY LGLY LGLY LGLY LGLY LGLY LGLY LGLY LGLY LTHR LTHR LTHR LTHR LTHR LTHR L

96969696969696969697979797979797989898989898989898989899999999100100100100101101101101102102102102102102

0.0870.093-0.764-0.702-1.239-1.169-2.094-2.022-2.4733.8744.8105.5305.6895.8216.4435.1235.9346.6308.0928.4466.0264.7163.5464.6482.3313.4282.2638.94410.34610.4499.55711.53211.72611.89411.85012.09612.24413.65014.58413.80915.09914.96614.24315.73616.027

7.3846.6678.5157.2738.4119.6059.34610.53810.4015.8305.6616.9287.8884.5684.8763.2636.9318.0677.7446.6128.4579.1698.47110.5349.10911.19210.4768.7488.5328.3968.8317.7927.5948.8628.8089.99311.26711.76110.98113.07513.63014.64315.62814.30213.300

0.438-0.7170.202-1.654-1.1150.978-1.6740.416-0.8972.6053.7024.1593.4003.3502.1063.1795.4236.0026.2566.5887.3507.2637.0107.5067.0097.5067.2606.1126.3897.8958.6228.3629.78410.58711.8099.91410.61110.96411.15611.04511.44712.59012.51310.2319.256

40.6832.6945.9535.9335.7346.8144.5741.4342.2822.7220.7725.0934.5512.2227.4316.8223.1726.7734.0840.2326.0123.1621.5922.3317.6630.1936.0337.9837.4834.9138.6836.8436.3034.7037.1137.3734.4331.9731.9526.3626.8833.1243.0027.4042.19

LLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLL

CCCNCCCCCNCCOCOCNCCOCCCCCCCNCCONCCONCCONCCOCO

807808809810811812813814815816817818819820821822823824825826827828829830831832833834835836837838839840841842843844845846847848849850851

CG2NCACOCBCGCDCENZNCACOCBCGCD1CD2NCACOCBCGCDOE1OE2NCACOCBCG1CG2CD1NCACOCBCGCDCENZN

THR LLYS LLYS LLYS LLYS LLYS LLYS LLYS LLYS LLYS LLEU LLEU LLEU LLEU LLEU LLEU LLEU LLEU LGLU LGLU LGLU LGLU LGLU LGLU LGLU LGLU LGLU LILE LILE LILE LILE LILE LILE LILE LILE LLYS LLYS LLYS LLYS LLYS LLYS LLYS LLYS LLYS LLYS L

102103103103103103103103103103104104104104104104104104105105105105105105105105105106106106106106106106106107107107107107107107107107108

17.04415.68015.64316.57317.74816.06914.99715.61014.87315.49815.99016.78116.98716.04616.02716.69818.03115.83018.23818.59619.42120.16919.38720.90121.55421.52522.08019.22919.88021.05420.93818.83318.11019.52016.79522.23523.42623.35923.42424.64524.96026.18526.51327.65023.271

14.98514.34415.23416.43516.30714.43314.41914.46013.56113.68917.63918.85619.53319.82819.79121.15621.06922.14019.75120.46121.71921.80419.50719.66319.58220.57018.51922.73724.01924.25824.18825.12325.38326.43224.61024.50524.73226.06527.14024.71623.31323.30221.89921.96525.992

10.64113.69114.84514.65514.34516.07517.16518.56719.56620.88214.81514.68416.04516.77013.73113.55912.81212.77216.43717.66417.37116.40418.56418.40719.76820.49120.10118.22917.98118.93320.14818.15416.82918.57916.72618.33119.14219.89219.31118.21917.69616.77816.26115.34421.213

27.0234.7537.6334.3642.5239.6160.5181.1589.9287.8435.1036.6233.7239.2240.9736.6643.7237.0741.1640.5437.8940.9542.3573.6884.8180.1787.5336.0442.0943.1441.0537.5547.0849.1853.8143.1642.2145.7852.8443.5641.4436.4060.7861.5851.53

LLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLL

CNCCOCCCCNNCCOCCCCNCCOCCCOONCCOCCCCNCCOCCCCNN

852853854855856857858859860861862863864865866867868869870871872873874875876877878879880881882883884885886887888889890891892893894895896

CACOCBCGCDCENZNCACOCBNCACOCBCGOD1OD2NCACOCBNCACOCBNCACOCBCGCDNCACOCBOG1CG2

LYS LLYS LLYS LLYS LLYS LLYS LLYS LLYS LALA LALA LALA LALA LALA LASP LASP LASP LASP LASP LASP LASP LASP LALA LALA LALA LALA LALA LALA LALA LALA LALA LALA LPRO LPRO LPRO LPRO LPRO LPRO LPRO LTHR LTHR LTHR LTHR LTHR LTHR LTHR L

108108108108108108108108109109109109109110110110110110110110110111111111111111112112112112112113113113113113113113114114114114114114114

23.24124.58525.44322.12522.05821.05921.13522.52524.77426.00025.84124.72826.17726.94426.90226.14226.24128.32029.00328.39630.16025.36824.59224.64424.58623.14824.77324.82523.42922.64725.75823.09021.77821.46022.35721.86823.32923.97320.16819.66719.18018.10318.47618.81418.088

27.16827.27926.39527.01528.13627.87128.95629.13928.37028.56727.74627.60830.03327.20026.39227.08228.29426.06025.02724.57424.66326.29426.79725.72624.53027.05226.15225.22725.07426.02925.74923.86223.54924.31824.74522.05421.86822.68924.48725.15123.96623.42626.03326.88226.872

22.06822.77922.65323.10624.09925.17826.23726.75423.51324.27325.53926.05224.62626.03927.25228.38528.58027.71526.82925.82627.14729.12030.24631.31531.00529.83232.56933.69434.24934.27634.77234.69635.26536.54237.26335.52735.83334.74936.79337.98338.80138.53937.65036.55538.835

46.0151.0452.8040.7740.5924.8444.4437.0452.7352.8952.6847.6755.4752.1148.4547.3643.9343.8258.5754.5862.2844.5639.6744.6849.0831.8146.6039.7541.1443.4936.8238.4339.8037.8239.6642.0035.8140.0435.1838.1040.5939.7340.4256.0439.90

LLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLL

CCOCCCCNNCCOCNCCOCCOONCCOCNCCOCNCCOCCCNCCOCOC

897898899900901902903904905906907908909910911912913914915916917918919920921922923924925926927928929930931932933934935936937938939940941

NCACOCBCG1CG2NCAC0CB0GNCACOCBCG1CG2CD1NCACOCBCGCD1CD2CE1CE2CZNCACOCBCGCDNCACOCBCG

VAL LVAL LVAL LVAL LVAL LVAL LVAL LSER LSER LSER LSER LSER LSER LILE LILE LILE LILE LILE LILE LILE LILE LPHE LPHE LPHE LPHE LPHE LPHE LPHE LPHE LPHE LPHE LPHE LPRO LPRO LPRO LPRO LPRO LPRO LPRO LPRO LPRO LPRO LPRO LPRO LPRO L

115115115115115115115116116116116116116117117117117117117117117118118118118118118118118118118118119119119119119119119120120120120120120

19.96619.60418.83919.17520.85520.46121.76717.79716.99716.43215.78715.86714.93616.69016.25914.99114.69017.39017.03917.64518.20514.25013.00112.78312.93111.81411.81712.71610.91212.71710.90911.81512.42112.16910.81910.00012.15112.94012.46710.5709.3128.1338.2439.55211.046

23.55522.38822.70423.63821.58720.22021.47821.92622.12420.78120.07123.13722.66820.44519.17819.31920.39518.58617.16019.48416.38418.22518.24717.03515.89518.35519.60019.75320.62120.89421.77121.90517.27816.22415.59116.18016.98518.23618.59714.38513.66514.38414.97212.32212.173

39.78740.57441.84042.55740.93641.42839.72442.11043.31443.76842.99443.06342.11445.03045.61146.44446.93446.47546.90247.65847.44846.59847.34748.24747.81246.38745.55344.51445.80643.74145.03143.99549.52350.51250.20849.50751.84051.54750.18050.73850.52451.14952.22451.20651.177

40.8638.0740.0549.0134.5534.9934.5042.2646.3344.2443.6444.7140.3845.4243.5342.4449.2641.5042.5233.2924.0241.5639.9342.6940.7235.4834.5018.8230.7632.1731.2225.1447.9647.9448.2954.1248.8544.7343.8245.7142.2445.1741.7442.9153.99

LLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLL

NCCOCCCNCCOCONCCOCCCCNCCOCCCCCCCNCCOCCCNCCOCC

942943944945946947948949950951952953954955956957958959960961962963964965966967968969970971972973974975976977978979980981982983984985986

CDNCACOCBOGNCACOCBOGNCACOCBCGCDOE1OE2NCACOCBCGCDOE1NE2NCACOCBCGCD1CD2NCACOCBOG1

PRO LSER LSER LSER LSER LSER LSER LSER LSER LSER LSER LSER LSER LGLU LGLU LGLU LGLU LGLU LGLU LGLU LGLU LGLU LGLN LGLN LGLN LGLN LGLN LGLN LGLN LGLN LGLN LLEU LLEU LLEU LLEU LLEU LLEU LLEU LLEU LTHR LTHR LTHR LTHR LTHR LTHR L

120121121121121121121122122122122122122123123123123123123123123123124124124124124124124124124125125125125125125125125126126126126126126

11.5167.0005.7835.3045.4264.7144.3524.7754.2703.1552.9853.7102.5952.4071.2981.7451.0920.6910.287-0.272-1.2460.2662.8563.3573.8683.7704.4905.2236.3726.9496.7304.4214.9553.8564.0205.6557.0417.6147.9552.7281.6251.3380.8250.341-0.109

13.56214.33314.94114.07212.84214.97213.65514.71113.97113.07211.93914.93815.63013.59712.88411.55210.53213.74515.10915.98115.55017.09511.55610.3119.4598.22910.5689.2979.54610.6368.53410.1319.4558.7327.57310.45610.87711.9939.6579.4058.7727.4576.5199.6439.818

51.50650.46450.97052.13252.10249.87849.49153.16854.31753.80254.25155.35154.81652.83852.22551.65751.85851.12951.63150.54549.89050.35150.93550.38451.53251.50549.40149.02848.10348.08747.32952.53753.70854.46354.85254.62654.13054.99754.13254.66655.37454.66555.25955.36254.015

48.0651.3752.6054.3156.7847.4554.1660.0059.8056.6861.4264.4374.5052.9154.3054.5957.0256.5670.5289.2682.9095.7555.0754.1252.4549.0455.7856.5750.0746.9951.3452.1255.4262.1863.1051.5058.4955.8041.5367.9174.1272.0774.1674.8789.50

LLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLL

CNCCOCONCCOCONCCOCCCOONCCOCCCONNCCOCCCCNCCOCO

98798898999099199299399499599699799899910001001100210031004100510061007100810091010101110121013101410151016101710181019102010211022102310241025102610271028102910301031

CG2NCACOCBOGNCACONCACONCACOCBNCACOCBOGNCACOCBCG1CG2NCACOCBCG1CG2NCACOCB

THR LSER LSER LSER LSER LSER LSER LGLY LGLY LGLY LGLY LGLY LGLY LGLY LGLY LALA LALA LALA LALA LALA LSER LSER LSER LSER LSER LSER LVAL LVAL LVAL LVAL LVAL LVAL LVAL LVAL LVAL LVAL LVAL LVAL LVAL LVAL LCYS LCYS LCYS LCYS LCYS L

126127127127127127127128128128128129129129129130130130130130131131131131131131132132132132132132132133133133133133133133134134134134134

0.6041.6901.4762.5432.3611.4341.4803.6554.7095.8686.7955.7766.7897.5407.0778.7119.50910.16210.85110.5639.91510.49811.22610.6649.4198.90412.49713.31113.46113.93514.66615.37314.47313.02313.11814.10714.33211.71611.85710.82214.72415.70515.52715.36817.102

11.0047.4016.2105.1363.9906.5975.4495.5084.5424.5983.7995.6305.7427.0517.9367.1628.3608.5747.6978.1889.73310.05711.38512.40210.1148.82011.35412.54312.88112.06612.23713.52011.31014.07014.45715.61016.40614.80915.35913.58115.66716.68917.18316.38816.104

55.98253.38652.57452.79452.40051.09350.26553.41753.67052.67052.70851.81550.78450.99451.71150.39050.51249.16948.65851.58648.58147.29747.39147.80746.21445.94947.03247.04945.57944.79747.65848.06248.83345.19143.79943.62944.53743.22541.83043.22642.46042.18940.75839.82942.397

77.0673.5474.0971.4168.1375.3579.2467.2863.1761.7155.6760.0151.5254.4756.9149.9843.2644.3644.3151.5144.5040.3743.3248.9538.7036.5238.4634.2239.0242.9738.3435.8845.8435.7135.5135.3932.9423.8227.7938.9138.3041.2942.6443.5138.37

LLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLL

CNCCOCONCCONCCONCCOCNCCOCONCCOCCCNCCOCCCNCCOC

103210331034103510361037103810391040104110421043104410451046104710481049105010511052105310541055105610571058105910601061106210631064106510661067106810691070107110721073107410751076

SGNCACOCBCGCD1CD2CE1CE2CZNCACOCBCGCD1CD2NCACOCBCGOD1ND2NCACOCBCGOD1ND2NCACOCBCGCD1CD2CE1

CYS LPHE LPHE LPHE LPHE LPHE LPHE LPHE LPHE LPHE LPHE LPHE LLEU LLEU LLEU LLEU LLEU LLEU LLEU LLEU LASN LASN LASN LASN LASN LASN LASN LASN LASN LASN LASN LASN LASN LASN LASN LASN LPHE LPHE LPHE LPHE LPHE LPHE LPHE LPHE LPHE L

134135135135135135135135135135135135136136136136136136136136137137137137137137137137138138138138138138138138139139139139139139139139139

18.39515.51915.36516.66917.42414.27612.87812.43411.99511.13210.69010.26116.92618.10317.50017.30219.09619.94019.07321.05017.18316.55417.38018.26915.32114.33413.48014.44417.04217.60719.15319.81917.11115.61515.09514.90619.75821.20821.58420.72721.77721.17721.54520.19220.941

17.35518.50219.10619.73220.27720.19319.66418.65220.19718.17719.72618.71119.62020.18420.85620.23219.07618.49717.68417.62622.13422.85123.82224.51123.56322.60123.00121.32823.84324.76024.74825.73826.17326.15026.13826.13923.64023.59023.27522.95022.52921.17420.37320.72619.152

42.64240.59039.27038.82039.61639.26839.38138.54640.31338.63540.40839.56337.53036.90735.68034.63836.52237.67438.63937.11435.81534.72333.89134.38235.26035.89436.68135.54532.60931.60131.53331.80931.91332.09333.20530.95131.13631.02829.57728.75631.99231.81430.74632.67730.533

65.3742.8338.0435.3838.8034.7431.5532.1835.7631.5627.9330.8331.8131.5835.5934.8529.5539.5928.4833.0835.6635.5030.5731.6839.8935.3534.8034.0033.9238.6041.4048.4236.3734.0752.4545.4936.8836.9638.9931.9634.9622.7128.8530.1926.26

LLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLL

SNCCOCCCCCCCNCCOCCCCNCCOCCONNCCOCCONNCCOCCCCC

107710781079108010811082108310841085108610871088108910901091109210931094109510961097109810991100110111021103110411051106110711081109111011111112111311141115111611171118111911201121

CE2CZNCACOCBCGCD1CD2CE1CE2CZOHNCACOCBCGCDNCACOCBCGCDCENZNCACOCBCGOD1OD2NCACOCBCG1CG2

PHE LPHE LTYR LTYR LTYR LTYR LTYR LTYR LTYR LTYR LTYR LTYR LTYR LTYR LPRO LPRO LPRO LPRO LPRO LPRO LPRO LLYS LLYS LLYS LLYS LLYS LLYS LLYS LLYS LLYS LASP LASP LASP LASP LASP LASP LASP LASP LILE LILE LILE LILE LILE LILE LILE L

139139140140140140140140140140140140140140141141141141141141141142142142142142142142142142143143143143143143143143144144144144144144144

19.57919.95222.86523.30824.81125.56022.90323.23924.53822.27424.87522.60023.91024.27325.27424.45123.68823.70225.46626.68926.70623.03722.05522.71422.06821.24822.14121.34521.85323.16824.04424.76325.07625.81126.07025.78725.95825.43224.46024.74024.48123.74623.85224.18722.377

19.50418.71223.38923.10522.90423.66724.24423.95024.07423.46523.72223.10423.23322.86421.88320.95019.90319.93420.32520.27121.61818.96818.05916.95416.21617.43916.75715.84515.89915.26916.82515.76816.16317.10215.49314.67815.22413.50715.42515.67814.43713.52916.82817.18816.390

32.47631.40129.25727.90827.88428.49526.96025.51925.05724.64523.78023.35322.92721.65127.14826.36527.18528.41425.41426.25626.93726.49427.07327.90828.64225.93124.89223.95722.51222.42727.74528.45329.90230.18027.70526.45225.36226.57530.84532.25533.11032.74332.73034.18132.685

29.0229.3944.6742.7842.6040.3439.6638.6238.5241.6840.6242.8848.7452.9343.9246.6549.8056.0145.6641.1645.2947.1650.4949.2752.2747.7363.0258.3573.1596.2450.4355.2453.0660.1258.4574.5087.1296.7949.8443.9444.6746.3447.2639.5527.85

LLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLL

CCNCCOCCCCCCCONCCOCCCNCCOCCCCNNCCOCCOONCCOCCC

112211231124112511261127112811291130113111321133113411351136113711381139114011411142114311441145114611471148114911501151115211531154115511561157115811591160116111621163116411651166

CD1NCACOCBCGOD1ND2NCACOCBCG1CG2NCACOCBCGCDCENZNCACOCBCGCD1CD2NE1CE2CE3CZ2CZ3CH2NCACOCBCG

ILE LASN LASN LASN LASN LASN LASN LASN LASN LVAL LVAL LVAL LVAL LVAL LVAL LVAL LLYS LLYS LLYS LLYS LLYS LLYS LLYS LLYS LLYS LTRP LTRP LTRP LTRP LTRP LTRP LTRP LTRP LTRP LTRP LTRP LTRP LTRP LTRP LLYS LLYS LLYS LLYS LLYS LLYS L

144145145145145145145145145146146146146146146146147147147147147147147147147148148148148148148148148148148148148148148149149149149149149

23.50325.15324.97724.54324.97126.30826.69225.87527.99223.62723.22023.64623.66521.70021.22221.29124.01924.43423.75723.82925.95226.52127.99428.88329.94923.05122.37123.30524.07621.06519.94019.56419.02918.46918.12118.88717.08617.85816.97123.24124.07223.26022.58225.26726.501

18.48014.40213.26313.70314.72212.51411.99411.46312.13712.90713.15312.00010.84013.30513.42014.55212.32211.30811.58712.68011.40210.23810.44810.59711.56110.59110.75610.2509.3229.96410.60110.34611.58611.10711.87912.24712.80713.16213.43410.88310.50410.57211.56011.45411.060

34.63634.27435.16736.56537.09735.25733.89633.14833.58237.14438.52139.43239.04338.55039.99637.78840.65741.58042.89343.43941.74442.55942.91841.67941.95043.41044.68245.75145.52944.72743.96842.67744.46442.34443.42245.68743.57045.83144.77846.91148.03649.31349.55448.16247.373

37.0047.8656.1948.4151.9058.1779.5874.9899.9247.1441.8041.2741.1338.5748.7052.2339.2943.6843.4347.0843.4149.0069.5679.1985.3649.1945.1945.9143.9739.6642.6133.0642.8230.8435.6632.8429.8840.2226.0147.4041.2239.9749.0439.1935.97

LLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLL

CNCCOCCONNCCOCCCNCCOCCCCNNCCOCCCCNCCCCCNCCOCC

116711681169117011711172117311741175117611771178117911801181118211831184118511861187118811891190119111921193119411951196119711981199120012011202120312041205120612071208120912101211

CDCENZNCACOCBCG1CG2CD1NCACOCBCGOD1OD2NCACONCACOCBOGNCACOCBCGCDOE1OE2NCACOCBCGCD

LYS LLYS LLYS LILE LILE LILE LILE LILE LILE LILE LILE LASP LASP LASP LASP LASP LASP LASP LASP LGLY LGLY LGLY LGLY LSER LSER LSER LSER LSER LSER LGLU LGLU LGLU LGLU LGLU LGLU LGLU LGLU LGLU LARG LARG LARG LARG LARG LARG LARG L

149149149150150150150150150150150151151151151151151151151152152152152153153153153153153154154154154154154154154154155155155155155155155

27.67928.98230.15623.30922.60623.62424.24021.50120.48320.83419.31923.79924.76326.17526.96424.40823.25522.80022.80626.47727.81927.93828.78327.07727.16326.35725.29426.63427.61226.92926.19725.11725.27327.19426.58227.46428.67426.92823.97722.91022.73922.79021.58421.48921.711

11.91711.46612.1829.5249.5449.2858.2278.4858.7008.5657.73010.26310.1629.9859.1809.0019.32810.4908.43410.74410.6659.5829.6298.5547.4407.6948.2996.1895.7157.2457.3336.2535.1367.1676.4596.6776.5846.9576.5895.6155.4636.4466.0755.9654.544

47.81747.18147.75950.12251.39652.49852.54651.47650.35152.84550.35053.37954.46853.92054.42255.39556.30756.28957.04852.87352.28751.20350.32251.31250.37149.09549.10651.08252.00947.96346.70346.61547.08845.55344.34043.12643.25242.05946.01945.80444.29343.55446.41847.93848.452

45.3770.5167.8138.1638.6239.3842.3435.5234.0030.4921.5642.1643.0847.3955.2138.7641.7653.0549.4148.8746.3749.7758.1848.0152.8345.6849.1154.7969.5843.3850.2949.8756.5745.6753.3172.0356.0170.3449.2747.4248.1549.7245.7846.2944.74

LLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLL

CCNNCCOCCCCNCCOCCOONCCONCCOCONCCOCCCOONCCOCCC

121212131214121512161217121812191220122112221223122412251226122712281229123012311232123312341235123612371238123912401241124212431244124512461247124812491250125112521253125412551256

NECZNH1NH2NCACOCBCGCDOE1NE2NCACOCBCGOD1ND2NCACONCACOCBCG1CG2NCACOCBCGCD1CD2NCACOCB

ARG LARG LARG LARG LGLN LGLN LGLN LGLN LGLN LGLN LGLN LGLN LGLN LASN LASN LASN LASN LASN LASN LASN LASN LGLY LGLY LGLY LGLY LVAL LVAL LVAL LVAL LVAL LVAL LVAL LLEU LLEU LLEU LLEU LLEU LLEU LLEU LLEU LASN LASN LASN LASN LASN L

155155155155156156156156156156156156156157157157157157157157157158158158158159159159159159159159160160160160160160160160161161161161161

21.59320.45019.31420.43422.55922.37521.00220.34323.39224.81325.45925.40126.07220.58419.32318.10418.18519.43420.75420.93521.68916.97815.74315.63114.88216.36416.27815.79416.19617.63118.72817.80414.90314.38114.53914.18912.92012.71211.22313.38015.11015.38314.52414.14916.828

4.4814.3134.1734.3234.2303.9563.3593.5852.9333.4042.7361.5143.5412.5831.8812.7293.6620.668-0.097-0.7970.0602.4023.1134.5145.3284.8186.1436.0965.2386.8555.8397.7097.0127.0888.5259.4736.6215.1384.8314.2298.6619.94910.1929.26510.007

49.90850.56549.90251.88843.83642.41642.20541.19741.91441.73040.52240.36439.65843.18843.13443.47544.26344.06043.85642.85244.80042.85243.11342.55643.08641.49640.92139.48938.71740.95441.06039.68939.14237.79237.29837.99637.75538.10838.13237.10336.10435.47934.26033.55935.003

46.0347.6857.0044.3547.0050.5048.5147.8257.5769.4287.9794.8596.0350.7556.0651.0154.5363.7577.5783.5079.7746.8236.6133.1137.6633.4037.2039.7950.8837.6041.2935.0540.6340.0135.4835.8041.1047.8464.8043.0833.9032.6433.5038.4338.36

LLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLL

NCNNNCCOCCCONNCCOCCONNCCONCCOCCCNCCOCCCCNCCOC

125712581259126012611262126312641265126612671268126912701271127212731274127512761277127812791280128112821283128412851286128712881289129012911292129312941295129612971298129913001301

CGOD1ND2NCACOCBOGNCACOCBCGCD1CD2NE1CE2CE3CZ2CZ3CH2NCACOCBOG1CG2NCACOCBCGOD1OD2NCACOCBCGCD

ASN LASN LASN LSER LSER LSER LSER LSER LSER LTRP LTRP LTRP LTRP LTRP LTRP LTRP LTRP LTRP LTRP LTRP LTRP LTRP LTRP LTHR LTHR LTHR LTHR LTHR LTHR LTHR LASP LASP LASP LASP LASP LASP LASP LASP LGLN LGLN LGLN LGLN LGLN LGLN LGLN L

161161161162162162162162162163163163163163163163163163163163163163163164164164164164164164165165165165165165165165166166166166166166166

17.82317.83918.67814.24913.46214.02714.44712.00611.19114.05414.58613.55612.87115.81716.95018.06017.09318.88618.31716.30418.77416.76117.98313.46312.53113.18014.37912.21513.42911.54912.39312.96613.61413.49311.89011.47910.64511.99814.29414.92113.88212.91715.92716.56617.735

9.76210.4638.76911.45211.77713.04013.95611.97211.99113.08814.26214.87514.16713.88813.33113.99911.98113.14611.89910.82910.7129.6449.59816.19916.91617.11916.91118.29219.02318.16517.49917.78019.15519.81517.83516.46415.81816.03319.61520.92322.03122.00121.13022.49222.524

36.10137.11135.90233.97632.80032.15332.84533.19432.04630.82930.13129.20628.46829.29330.08430.51430.53431.20131.22730.41931.80130.99631.67529.23528.37727.01326.86728.95529.11130.29926.00924.69024.80725.83223.59723.10523.76922.05223.77223.88423.89023.12622.75422.71621.767

37.2640.0632.1531.1226.4328.8933.5922.5037.3733.4428.6327.8133.2528.1130.7234.8137.1231.2436.5942.1344.4049.8329.3127.8329.4727.5732.9729.6625.2333.2032.3037.7534.7641.0544.2945.3254.6165.6634.8933.1134.3340.7332.3425.9424.29

LLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLL

CONNCCOCONCCOCCCCNCCCCCNCCOCOCNCCOCCOONCCOCCC

130213031304130513061307130813091310131113121313131413151316131713181319132013211322132313241325132613271328132913301331133213331334133513361337133813391340134113421343134413451346

OE1NE2NCACOCBCGOD1OD2NCACOCBOGNCACOCBCGCDCENZNCACOCBCGOD1OD2NCACOCBOGNCACOCBOG1

GLN LGLN LASP LASP LASP LASP LASP LASP LASP LASP LSER LSER LSER LSER LSER LSER LLYS LLYS LLYS LLYS LLYS LLYS LLYS LLYS LLYS LASP LASP LASP LASP LASP LASP LASP LASP LSER LSER LSER LSER LSER LSER LTHR LTHR LTHR LTHR LTHR LTHR L

166166167167167167167167167167168168168168168168169169169169169169169169169170170170170170170170170171171171171171171172172172172172172

17.69118.78914.08413.24413.13314.08913.86912.82511.84313.00311.90711.71112.00211.96510.26810.17212.27912.47613.93814.52411.59610.2269.2327.9807.42514.51415.92216.81317.96716.05315.57415.49915.29616.20916.98317.84519.05717.87217.05317.18917.92117.39916.46617.78316.404

21.91523.23423.00024.18324.91925.04425.10226.10425.66527.30125.37326.04127.54228.26725.80224.51428.00929.44029.81030.64129.89630.37130.58531.35132.10129.20029.46628.25528.17029.87828.74327.62028.98827.27126.13325.48525.35126.62826.97425.10024.40722.98222.53525.20725.512

20.70322.14124.77524.91123.57822.82625.96526.43827.04126.21423.26521.98522.06721.08221.53520.92223.30123.49123.74623.06524.65424.16425.30724.85825.98724.79925.09124.79025.19326.56027.45526.96228.62724.09623.60724.69224.56322.46721.34825.80326.85627.05926.40528.15228.370

29.0339.5436.2637.7738.9845.8439.0150.6261.3065.6039.9136.4136.7442.8234.5538.7041.0040.7144.3147.3850.4064.2592.3799.8694.6045.9746.9043.2847.7848.0048.0351.4584.9746.8648.3548.3755.9945.2060.9751.3444.7842.1745.9737.8557.23

LLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLL

ONNCCOCCOONCCOCONCCOCCCCNNCCOCCOONCCOCONCCOCO

134713481349135013511352135313541355135613571358135913601361136213631364136513661367136813691370137113721373137413751376137713781379138013811382138313841385138613871388138913901391

CG2NCACOCBCGCD1CD2CE1CE2CZOHNCACOCBOGNCACOCBCGSDCENCACOCBOGNCACOCBOGNCACOCBOG1

THR LTYR LTYR LTYR LTYR LTYR LTYR LTYR LTYR LTYR LTYR LTYR LTYR LSER LSER LSER LSER LSER LSER LMET LMET LMET LMET LMET LMET LMET LMET LSER LSER LSER LSER LSER LSER LSER LSER LSER LSER LSER LSER LTHR LTHR LTHR LTHR LTHR LTHR L

172173173173173173173173173173173173173174174174174174174175175175175175175175175176176176176176176177177177177177177178178178178178178

18.57717.89217.36417.22818.07018.29918.55119.52817.88619.84718.19419.17919.53316.17215.93215.82015.36314.64414.72316.26416.18515.65815.93117.55518.06518.88517.71814.87214.28514.79414.96812.76612.14015.04415.50914.78714.51117.00417.48014.50013.78314.37814.52712.30311.700

26.51722.28820.99320.91921.43219.87719.77320.54218.81820.34718.62319.38219.12420.26120.10318.62417.84020.81722.19118.23516.84816.79817.67516.16915.62214.02212.95615.76915.55314.21113.25615.52615.05514.13712.88712.49213.32512.93911.61811.20510.7449.4978.46010.45211.620

28.05028.06928.44229.94730.67928.01426.54425.93125.78124.60524.46823.88422.58730.39631.81032.10331.27032.21031.87233.28333.66535.08335.89533.57634.89034.68535.39535.35236.65037.16736.38836.51037.68038.47339.06040.34941.21639.30639.25740.48041.64642.28741.64441.28840.726

33.6844.0840.5040.1440.8832.4038.4423.3430.4523.6423.6131.6450.6132.2533.2531.1435.7434.9644.2132.4533.6536.0337.6034.5133.1750.7951.7738.2830.7933.0036.3529.6025.8534.2031.3030.6034.6122.1735.6428.8328.1233.5634.1929.0734.69

LLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLL

CNCCOCCCCCCCONCCOCONCCOCCSCNCCOCONCCOCONCCOCO

139213931394139513961397139813991400140114021403140414051406140714081409141014111412141314141415141614171418141914201421142214231424142514261427142814291430143114321433143414351436

CG2NCACOCBCGCD1CD2NCACOCBOG1CG2NCACOCBCGCD1CD2NCACOCBOG1CG2NCACOCBCGCDCENZNCACOCB

THR LLEU LLEU LLEU LLEU LLEU LLEU LLEU LLEU LTHR LTHR LTHR LTHR LTHR LTHR LTHR LLEU LLEU LLEU LLEU LLEU LLEU LLEU LLEU LTHR LTHR LTHR LTHR LTHR LTHR LTHR LLYS LLYS LLYS LLYS LLYS LLYS LLYS LLYS LLYS LASP LASP LASP LASP LASP L

178179179179179179179179179180180180180180180180181181181181181181181181182182182182182182182183183183183183183183183183184184184184184

11.52614.71715.23814.13313.80316.51316.93716.87718.33113.54912.47813.01713.87411.42010.98310.22712.50212.89611.62610.58013.72014.85415.41115.92911.71610.57110.63911.71710.73311.87910.9149.5079.46510.48110.8698.0497.8406.6176.7715.65410.91311.81113.23713.80711.809

10.0509.6098.4788.0728.8138.8527.7116.3987.9646.9056.4535.5734.7125.6606.4375.3385.7965.0434.6605.2415.9206.7217.6995.7723.6753.2764.2664.7761.8381.7860.8324.5405.4725.1045.9515.5216.6436.4175.1524.9413.8433.4163.9304.6491.885

42.52043.56544.31345.29446.21945.07646.01345.26546.56845.08345.94747.05946.82845.15544.03346.03248.26449.44050.16149.91750.37549.75050.77249.24351.04451.85753.02353.33652.42353.28751.30853.66254.79355.89856.71155.38756.38557.25558.08959.05655.91756.98456.76357.57357.027

38.6637.1337.3638.6746.2238.3339.8136.1242.7535.6640.7046.9155.3542.8153.1140.3644.6838.1842.6547.0436.5635.7923.7948.4449.6145.2240.8941.0047.8053.7550.2345.5448.1151.2049.3043.2840.5066.9277.9473.2452.4553.0248.7351.8557.50

LLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLL

CNCCOCCCCNCCOCOCNCCOCCCCNCCOCOCNCCOCCCCNNCCOC

143714381439144014411442144314441445144614471448144914501451145214531454145514561457145814591460146114621463146414651466146714681469147014711472147314741475147614771478147914801481

CGOD1OD2NCACOCBCGCDOE1OE2NCACOCBCGCD1CD2CE1CE2CZOHNCACOCBCGCDOE1OE2NCACOCBCGCDNECZNH1NH2N

ASP LASP LASP LGLU LGLU LGLU LGLU LGLU LGLU LGLU LGLU LGLU LTYR LTYR LTYR LTYR LTYR LTYR LTYR LTYR LTYR LTYR LTYR LTYR LGLU LGLU LGLU LGLU LGLU LGLU LGLU LGLU LGLU LARG LARG LARG LARG LARG LARG LARG LARG LARG LARG LARG LHIS L

184184184185185185185185185185185185186186186186186186186186186186186186187187187187187187187187187188188188188188188188188188188188189

10.70510.09910.46013.83215.18515.28616.24615.56616.94518.01517.69919.16614.26214.23314.36615.06812.90912.82313.82211.77813.77911.74012.73912.71013.69513.79015.08515.51012.57311.36810.0449.9069.13515.72516.96518.13119.23517.26916.21616.72318.04918.25717.22019.49617.890

1.4072.2570.2053.4973.9445.4706.0603.4063.8893.0772.3843.1406.1137.5708.1129.0818.0289.51410.28110.14611.66511.52912.28713.6657.5107.9817.5498.1567.5038.3957.6666.8327.9436.5126.0296.9346.7674.6233.5852.2552.0091.5071.1871.3577.882

57.96058.61258.02155.63555.32355.33455.81353.94353.49254.18655.14453.75654.74154.75456.17956.44254.14054.17753.58254.85153.66354.94054.35854.44657.14758.52059.20260.17659.30659.08559.22360.15058.40558.67559.25258.89059.40658.75459.05058.54559.09860.30761.06960.76157.993

71.4466.1681.9143.1042.1345.2250.2243.0822.8839.6247.9753.0742.1240.4440.3346.6441.3238.8529.7237.4128.9032.4130.1042.6244.4946.8748.7050.9142.2262.9686.2380.1994.4046.2844.5246.6652.7348.2958.2665.0763.5866.1354.3356.1044.20

LLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLL

COONCCOCCCOONCCOCCCCCCCONCCOCCCOONCCOCCCNCNNN

148214831484148514861487148814891490149114921493149414951496149714981499150015011502150315041505150615071508150915101511151215131514151515161517151815191520152115221523152415251526

CACOCBCGND1CD2CE1NE2NCACOCBCGOD1ND2NCACOCBOGNCACOCBCGCD1CD2CE1CE2CZOHNCACOCBOG1CG2NCAC

HIS LHIS LHIS LHIS LHIS LHIS LHIS LHIS LHIS LASN LASN LASN LASN LASN LASN LASN LASN LSER LSER LSER LSER LSER LSER LTYR LTYR LTYR LTYR LTYR LTYR LTYR LTYR LTYR LTYR LTYR LTYR LTHR LTHR LTHR LTHR LTHR LTHR LTHR LCYS LCYS LCYS L

189189189189189189189189189190190190190190190190190191191191191191191192192192192192192192192192192192192193193193193193193193194194194

18.89718.50517.41419.03719.69320.95319.09321.10020.00019.45519.22119.74719.22919.86520.19419.34321.51220.83521.34821.08221.64822.85523.35620.29220.04020.65020.32118.53717.94817.89617.51817.44217.06117.02616.56721.55122.25022.08322.09123.75624.03624.58721.95821.80422.924

8.76410.23110.5568.4297.0716.8135.8575.4774.87711.13812.51913.53114.62712.71014.16014.99114.43513.14413.98513.35812.33014.13815.07714.05613.64314.65515.83513.50712.43812.60011.23911.59710.23110.4129.38714.17515.02314.66513.50115.05616.17215.16815.70815.59516.422

57.42757.64558.09355.93555.78556.20855.44356.14055.68557.35457.74856.72856.57359.12259.39559.71059.36556.03954.96553.59753.24555.16054.20452.79051.41450.46550.50851.18752.07753.45951.54654.27552.35753.71854.50049.61448.67347.21246.82448.99349.83747.71746.40744.97144.319

42.6245.8946.2645.7340.1951.0059.8347.5061.6650.7355.4753.4362.9857.6071.5984.2674.5648.5748.4348.7649.9548.7958.5948.1345.1142.9638.3445.1842.7722.5638.3125.4044.5437.8932.0145.2145.1844.1845.2247.9749.8656.5545.7845.4541.02

LLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLL

CCOCCNCCNNCCOCCONNCCOCONCCOCCCCCCCONCCOCOCNCC

152715281529153015311532153315341535153615371538153915401541154215431544154515461547154815491550155115521553155415551556155715581559156015611562156315641565156615671568156915701571

OCBSGNCACOCBCGCDOE1OE2NCACOCBNCACOCBOG1CG2NCACOCBCGND1CD2CE1NE2NCACOCBCGCDCENZNCA

CYS LCYS LCYS LGLU LGLU LGLU LGLU LGLU LGLU LGLU LGLU LGLU LALA LALA LALA LALA LALA LTHR LTHR LTHR LTHR LTHR LTHR LTHR LHIS LHIS LHIS LHIS LHIS LHIS LHIS LHIS LHIS LHIS LLYS LLYS LLYS LLYS LLYS LLYS LLYS LLYS LLYS LTHR LTHR L

194194194195195195195195195195195195196196196196196197197197197197197197198198198198198198198198198198199199199199199199199199199200200

23.00220.41120.13323.79824.90924.83724.67026.24626.36727.79728.56928.14524.99024.93826.31527.06023.99026.64427.93827.70727.15428.72328.65630.17728.13527.95829.24429.99226.76926.39626.28426.06825.90425.76429.50130.70830.88331.99030.73529.63129.88631.15231.31029.80729.900

17.62716.11816.30015.77216.46716.41415.34715.86915.58315.28214.79615.52217.56817.63917.87318.74018.74717.09617.21017.57616.79515.87915.32916.11318.77019.25519.94420.49020.22620.69219.83421.92120.51521.78319.91720.52621.99822.52920.38321.13621.21121.99122.20822.66224.074

44.52544.58442.80443.55142.89341.36640.78243.32644.81045.22144.36446.40140.72339.26738.67039.12338.82737.64236.97635.51934.75637.03238.35736.66835.14133.78333.32734.14333.75032.37631.30231.91230.23630.57932.02531.48431.85131.76829.96529.26227.76827.46325.99332.25632.613

44.6445.4069.2139.8042.6741.7036.4246.0164.7773.0056.3272.7240.1342.3847.4245.4340.8554.2756.9752.1254.8660.4455.7966.9852.5449.0550.3151.3848.3255.9061.3645.2864.7254.4154.0353.0055.0959.8051.5354.5069.2789.2198.4252.5055.94

LLLLLLLLLLLL1LLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLL

OCSNCCOCCCOONCCOCNCCOCOCNCCOCCNCCNNCCOCCCCNNC

157215731574157515761577157815791580158115821583158415851586158715881589159015911592159315941595159615971598159916001601160216031604160516061607160816091610161116121613161416151616

COCB0G1CG2NCACOCBOGNCACOCBOG1CG2NCACOCBOGNCACOCBCGCDNCACOCBCG1CG2CD1NCACOCBCG1

THR LTHR LTHR LTHR LTHR LSER LSER LSER LSER LSER LSER LTHR LTHR LTHR LTHR LTHR LTHR LTHR LSER LSER LSER LSER LSER LSER LPRO LPRO LPRO LPRO LPRO LPRO LPRO LILE LILE LILE LILE LILE LILE LILE LILE LVAL LVAL LVAL LVAL LVAL LVAL L

200200200200200201201201201201201202202202202202202202203203203203203203204204204204204204204205205205205205205205205206206206206206206

30.72730.78828.51327.73127.83031.35932.18832.91632.60431.34130.35633.89234.68734.14134.21636.15836.21736.86133.59933.02031.52630.82933.22932.82531.01829.59528.71229.05229.49330.50231.68727.58826.64025.88625.08625.65626.43124.69425.54926.14725.52524.37824.46526.58425.967

24.35125.48624.68623.83424.86423.31323.45322.15921.08923.88522.91722.27321.13120.55719.35321.53622.78321.66521.42720.99720.73221.52422.07823.35819.60519.29720.23720.61017.85317.82118.55420.62721.50920.66219.80122.09422.81723.03923.57920.90920.11820.80321.96519.66618.715

33.87134.34732.80333.64331.47334.40735.59935.93835.40936.79237.08636.82837.26738.56838.80837.47338.18836.12339.40940.67340.46239.83241.74341.27440.97940.80841.60642.72241.29642.39341.76541.01641.67842.69642.33340.67239.57841.37138.62043.97245.01745.74346.11446.05847.046

59.7266.1548.3759.0453.6562.1363.3961.3360.6461.7476.7863.7768.8069.4269.2672.0666.1868.7771.1374.4771.1569.3676.7581.9967.6962.6156.9762.7456.9766.2970.4151.6846.3245.8040.0545.7142.6048.1557.3042.2745.0143.4854.3742.2948.63

LLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLL

COCOCNCCOCONCCOCOCNCCOCONCCOCCCNCCOCCCCNCCOCC

161716181619162016211622162316241625162616271628162916301631163216331634163516361637163816391640164116421643164416451646164716481649165016511652165316541655165616571658165916601661

CG2NCACOCBCGCDCENZNCACOCBOGNCACOCBCGCD1CD2CE1CE2CZNCACOCBCGOD1ND2NCACOCBCGCDNECZNH1

VAL LLYS LLYS LLYS LLYS LLYS LLYS LLYS LLYS LLYS LSER LSER LSER LSER LSER LSER LPHE LPHE LPHE LPHE LPHE LPHE LPHE LPHE LPHE LPHE LPHE LASN LASN LASN LASN LASN LASN LASN LASN LARG LARG LARG LARG LARG LARG LARG LARG LARG LARG L

206207207207207207207207207207208208208208208208209209209209209209209209209209209210210210210210210210210211211211211211211211211211211

27.75023.29622.13021.68921.69521.00321.28321.39521.73821.87221.29620.88920.14920.20322.11723.07819.46618.71118.91419.45317.22716.60216.19416.43415.63015.87015.46918.48718.58817.19316.45019.46220.93521.63521.41016.83515.53115.28014.14715.46814.11414.21015.23115.00313.779

18.99220.06420.56919.47818.30220.88622.06323.35724.50525.79819.85918.85619.43220.62718.10319.00518.55018.93317.89416.81519.03817.72816.83617.38015.62516.17215.29618.22817.30217.00817.91217.88817.68117.05918.18515.73215.30215.83516.16913.78113.21111.71311.29111.06611.217

45.35845.93146.63147.58447.23845.65444.75045.53244.59845.31048.78749.74750.93151.19850.24350.76351.64652.82253.92353.68852.46452.09153.06450.76152.71450.41151.38655.13156.24256.76157.13057.34357.07357.86455.93556.76257.23158.63158.98357.24757.58657.61458.56559.85560.349

38.4741.4345.7145.0346.0449.3755.0764.9671.8178.5344.0249.8050.9453.7053.5159.0751.9151.3449.6454.5949.2046.9037.5753.3447.3136.3734.6549.6046.6148.6343.7242.7660.0269.2375.7250.5354.1162.1163.8853.5644.4754.9158.2372.8273.06

LLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLL

CNCCOCCCCNNCCOCONCCOCCCCCCCNCCOCCONNCCOCCCNCN

原子原子TER原子原子原子原子原子原子原子原子原子原子原子原子原子原子原子原子原子原子原子原子原子原子原子原子原子原子原子原子原子原子原子原子原子原子原子原子原子原子原子原子原子原子

166216631664166516661667166816691670167116721673167416751676167716781679168016811682168316841685168616871688168916901691169216931694169516961697169816991700170117021703170417051706

NH2OXTNCACOCBCGCDOE1OE2NCACOCBCG1CG2NCACOCBCGCDCENZNCACOCBCGCD1CD2NCACOCBCG1CG2NCA

ARG LARG LARG LGLU HGLU HGLU HGLU HGLU HGLU HGLU HGLU HGLU HVAL HVAL HVAL HVAL HVAL HVAL HVAL HLYS HLYS HLYS HLYS HLYS HLYS HLYS HLYS HLYS HLEU HLEU HLEU HLEU HLEU HLEU HLEU HLEU HVAL HVAL HVAL HVAL HVAL HVAL HVAL HGLU HGLU H

211211211111111111222222233333333344444444555555566

16.00116.349-11.229-10.037-10.186-10.717-9.807-9.166-9.800-9.507-10.586-9.728-9.825-9.533-8.616-8.839-8.720-9.339-10.391-10.299-10.578-11.632-11.363-11.099-12.072-12.025-12.982-9.564-9.766-9.672-8.625-8.723-8.916-7.819-10.246-10.765-10.733-11.037-12.140-11.757-11.835-11.357-10.044-10.251

10.70315.91528.75128.15626.64226.14728.80827.84928.04729.04427.19225.87424.42723.83824.23423.90322.38424.26522.88922.35020.85020.38123.06823.02623.93523.73124.62920.08418.65018.14718.18517.97018.32317.72517.81717.69617.25115.77215.35018.02717.43719.48714.98713.552

60.65359.42110.62111.21411.37812.36412.57813.58214.94015.58415.34610.40410.38111.75912.4659.3389.4467.94812.15513.49613.49213.09114.32315.82916.58418.10218.74313.90613.97315.41116.04413.08311.60310.71811.04116.00717.38517.45317.14218.22519.60718.29617.84218.025

1.001.001.001.001.001.001.001.001.001.001.001.001.001.001.001.001.001.001.001.001.001.001.001.001.001.001.001.001.001.001.001.001.001.001.001.001.001.001.001.001.001.001.001.00

62.5969.0571.3665.3258.2657.6563.1971.0387.7395.8896.8456.3445.1140.3544.3246.7937.7232.9439.6340.7538.2946.1842.3553.4897.53126.21139.1436.6931.8236.9535.0627.4123.6929.8823.2243.6941.3538.9442.9537.9840.2432.8438.4543.30

LLHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH

NONCCOCCCOONCCOCCCNCCOCCCCNNCCOCCCCNCCOCCCNC

170717081709171017111712171317141715171617171718171917201721172217231724172517261727172817291730173117321733173417351736173717381739174017411742174317441745174617471748174917501751

COCBCGCDOE1OE2NCACOCBOGNCACONCACONCACONCACOCBCGCD1CD2NCACOCBCG1CG2NCACOCB

GLU HGLU HGLU HGLU HGLU HGLU HGLU HSER HSER HSER HSER HSER HSER HGLY HGLY HGLY HGLY HGLY HGLY HGLY HGLY HGLY HGLY HGLY HGLY HLEU HLEU HLEU HLEU HLEU HLEU HLEU HLEU HVAL HVAL HVAL HVAL HVAL HVAL HVAL HLYS HLYS HLYS HLYS HLYS H

666666677777788889999101010101111111111111111121212121212121313131313

-10.849-11.081-8.899-8.397-7.318-6.427-7.420-11.141-11.734-12.123-12.030-12.975-13.927-12.533-12.996-11.834-11.927-10.697-9.519-9.206-9.129-9.060-8.739-7.985-7.434-7.938-7.249-8.119-9.337-6.895-6.087-4.725-5.801-7.453-8.179-7.340-6.127-8.535-9.134-9.542-8.035-7.316-7.121-7.975-8.117

13.23814.11112.85512.87413.92213.84714.93411.94011.54210.0619.34712.40312.1499.5978.2177.2276.0627.7416.8886.5677.4345.2564.8343.5023.0542.8831.6100.4530.4481.4130.1370.166-0.113-0.533-1.712-2.973-2.931-1.535-2.832-0.414-4.121-5.381-6.008-5.934-6.324

19.39820.22517.87216.42816.28415.45417.16819.61320.88620.90219.91221.12220.08822.09822.22722.35521.99222.86122.99224.45625.31624.73126.09026.10125.10527.29527.42826.94027.06628.90329.14428.44330.62526.32425.88326.06326.22624.40723.86224.24526.07826.17424.79323.92027.071

47.1853.6038.5034.5428.6439.1529.2351.2153.0153.0644.6354.3545.6555.0256.7653.9855.0448.9049.8453.7260.0547.7252.6253.3453.7951.0242.3443.6544.2150.2036.2443.7559.3142.9443.1647.6657.8340.2946.8049.3945.7143.8940.3946.9845.28

HHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH

COCCCOONCCOCONCCONCCONCCONCCOCCCCNCCOCCCNCCOC

175217531754175517561757175817591760176117621763176417651766176717681769177017711772177317741775177617771778177917801781178217831784178517861787178817891790179117921793179417951796

CGCDCENZNCACOCBCGCDNCACONCACONCACOCBOGNCACOCBCGCD1CD2NCACOCBCGCDCENZNCAC

LYS HLYS HLYS HLYS HPRO HPRO HPRO HPRO HPRO HPRO HPRO HGLY HGLY HGLY HGLY HGLY HGLY HGLY HGLY HSER HSER HSER HSER HSER HSER HLEU HLEU HLEU HLEU HLEU HLEU HLEU HLEU HLYS HLYS HLYS HLYS HLYS HLYS HLYS HLYS HLYS HLEU HLEU HLEU H

131313131414141414141415151515161616161717171717171818181818181818191919191919191919202020

-7.818-8.511-7.655-6.458-5.976-5.784-6.971-7.434-4.496-4.370-4.849-7.466-8.601-9.828-10.789-9.782-10.913-11.219-10.566-12.238-12.700-12.735-12.910-14.090-14.056-12.582-12.573-13.007-12.778-11.155-10.925-11.722-9.449-13.640-13.988-13.744-14.Z88-15.465-15.854-17.256-18.247-19.100-13.082-12.538-13.376

-6.100-4.851-4.105-3.569-6.651-7.265-8.123-8.952-8.076-8.249-6.948-7.903-8.653-7.770-8.044-6.688-5.781-4.862-4.890-4.030-3.076-1.670-1.477-3.463-4.768-0.6900.7041.5161.0941.0832.4882.6662.7012.6653.4834.9715.5623.2473.8034.4163.6144.5295.3266.6627.653

28.55429.10230.13329.48624.54423.23122.83723.61723.40124.87725.43521.62421.11921.10320.38921.87521.95220.77519.72120.98619.99420.56621.76219.51318.96919.68820.08418.86117.72120.51221.05122.32121.30819.09017.93318.19819.12117.60816.23616.23515.38414.62917.24917.45016.679

67.3788.3380.9958.4038.8838.3244.4652.9937.3840.4235.0145.6739.6942.7343.4244.1643.3945.0434.8545.8544.2342.8843.4544.9764.6643.6142.0339.5239.6343.4142.3943.3659.3036.4742.7640.9942.2443.9656.0045.6859.4851.5539.7g36.6834.74

HHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH

CCCNNCCOCCCNCCONCCONCCOCONCCOCCCCNCCOCCCCNNCC

179717981799180018011802180318041805180618071808180918101811181218131814181518161817181818191820182118221823182418251826182718281829183018311832183318341835183618371838183918401841

OCBCGCD1CD2NCACOCBOGNCACOCBSGNCACOCBNCACOCBNCACOCBOGNCACONCACOCBCGCD1CD2

LEU HLEU HLEU HLEU HLEU HSER HSER HSER HSER HSER HSER HCYS HCYS HCYS HCYS HCYS HCYS HALA HALA HALA HALA HALA HALA HALA HALA HALA HALA HSER HSER HSER HSER HSER HSER HGLY HGLY HGLY HGLY HPHE HPHE HPHE HPHE HPHE HPHE HPHE HPHE H

202020202021212121212122222222222223232323232424242424252525252525262626262727272727272727

-14.020-11.096-9.905-8.614-9.778-13.497-14.281-13.489-12.563-15.634-15.449-13.846-13.155-14.158-14.810-12.135-11.198-14.284-15.187-14.445-13.378-15.552-14.992-14.362-15.091-16.200-14.379-14.456-15.040-14.022-12.823-15.509-14.401-14.510-13.627-13.361-12.549-14.035-13.856-15.015-15.759-12.522-12.394-12.133-12.547

7.3036.7796.0226.2716.4549.0059.91911.20211.46110.20410.83911.99713.24214.28514.17213.05714.51315.29816.40217.36417.89317.08917.57218.46519.80019.91017.83620.81122.14623.14222.99522.63722.99424.16325.18124.98025.68424.00723.74522.93022.34323.01721.67521.57020.512

15.69416.94517.53516.75918.97716.92716.12215.98316.75316.76818.00814.98814.73914.34613.31813.61213.00415.19014.92614.00214.34816.22012.81411.86711.85712.36810.48111.27511.17310.63810.86212.53513.3279.9439.4177.9517.3627.3565.9465.4276.2065.6706.3297.6915.586

33.3740.6441.1161.7135.5933.1940.5642.4144.6634.4246.9237.0638.1431.5430.6443.7355.5532.0331.5639.5637.6938.1736.8131.7634.3042.6629.2545.2245.4845.0448.3445.0538.9743.0436.8038.4952.8537.9334.0536.9139.0033.3417.4125.2915.22

HHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH

OCCCCNCCOCONCCOCSNCCOCNCCOCNCCOCONCCONCCOCCCC

184218431844184518461847184818491850185118521853185418551856185718581859186018611862186318641865186618671868186918701871187218731874187518761877187818791880188118821883188418851886

CE1CE2CZNCACOCBOG1CG2NCACOCBCGCD1CD2CE1CE2CZNCACOCBCG1CG2CD1NCACOCBOGNCACOCBCGCD1CD2CE1CE2

PHE HPHE HPHE HTHR HTHR HTHR HTHR HTHR HTHR HTHR HPHE HPHE HPHE HPHE HPHE HPHE HPHE HPHE HPHE HPHE HPHE HILE HILE HILE HILE HILE HILE HILE HILE HSER HSER HSER HSER HSER HSER HTYR HTYR HTYR HTYR HTYR HTYR HTYR HTYR HTYR HTYR H

272727282828282828282929292929292929292929303030303030303031313131313132323232323232323232

-12.030-12.447-12.188-15.168-16.238-15.956-15.657-16.349-16.428-17.575-16.063-15.818-16.163-15.391-16.530-16.417-17.427-15.298-17.325-15.189-16.205-17.316-17.752-16.860-16.809-19.182-19.637-19.225-21.038-16.153-15.332-13.914-13.159-15.304-16.600-13.570-12.240-12.172-13.125-11.622-11.220-10.063-11.997-9.692-11.633

20.31919.26519.16722.90722.17620.67520.04222.64524.07422.06620.13018.72117.67416.75518.39016.95416.05516.50514.74015.19314.30717.81316.87516.82415.80917.22016.25918.66316.51517.90717.91517.38617.30619.31919.71717.00116.48314.99814.41417.26518.65718.89519.73520.16521.001

8.3046.1887.5474.1083.4573.5202.5102.0071.9891.3404.7285.0423.9793.7306.3566.7716.4817.4626.8727.8557.5603.3472.3241.0800.3761.8670.7701.3560.3080.795-0.403-0.236-1.208-1.010-1.4170.9881.2731.6212.1262.4192.0561.3432.4180.9982.082

21.748.6716.9738.2035.3535.6241.3537.4641.2944.0334.2534.2234.2547.3733.1330.3333.7638.7241.2425.2131.2535.5736.5038.9540.3936.8435.1736.8443.8833.2837.1638.7639.0533.7241.2837.1035.9235.7535.0731.8131.6740.1127.9330.2643.25

HHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH

CCCNCCOCOCNCCOCCCCCCCNCCOCCCCNCCOCONCCOCCCCCC

188718881889189018911892189318941895189618971898189919001901190219031904190519061907190819091910191119121913191419151916191719181919192019211922192319241925192619271928192919301931

CZOHNCACOCBNCACOCBCGSDCENCACOCBOGNCACOCBCGCD1CD2NE1CE2CE3CZ2CZ3CH2NCACOCBCG1CG2NCAC

TYR HTYR HALA HALA HALA HALA HALA HMET HMET HMET HMET HMET HMET HMET HMET HSER HSER HSER HSER HSER HSER HTRP HTRP HTRP HTRP HTRP HTRP HTRP HTRP HTRP HTRP HTRP HTRP HTRP HTRP HVAL HVAL HVAL HVAL HVAL HVAL HVAL HARG HARG HARG H

323233333333333434343434343434353535353535363636363636363636363636363637373737373737383838

-10.475-10.103-11.024-10.781-10.282-9.672-9.707-10.556-10.120-9.231-9.373-11.324-12.122-11.099-10.854-8.308-7.391-7.009-7.102-6.118-6.378-6.591-6.130-4.651-4.286-6.945-8.340-9.498-8.710-10.565-10.109-7.994-10.809-8.687-10.081-3.802-2.369-1.922-2.258-1.537-0.087-2.043-1.164-0.7360.766

21.21422.49314.39913.01013.12514.13112.43312.11612.14710.9589.91712.14713.43614.93314.93911.11310.0359.89010.82810.20010.0128.6868.4418.0417.2107.3247.7247.5468.3488.0168.5128.7809.0899.3559.5028.6648.3678.2149.0329.5079.1029.8467.1787.0187.128

1.3681.0261.3261.6573.0843.4460.7793.8995.2835.5554.9216.2266.1806.4198.1756.4976.8088.2659.0455.9904.6128.6319.9809.8639.02910.64311.08010.38612.31911.11212.30313.44313.36514.50114.45410.67010.67212.11512.96810.0529.9988.67012.41413.79613.979

39.7165.7333.2535.6136.2731.7728.4133.2728.4928.0027.8131.2430.3239.2017.5528.9024.8933.4435.0221.6832.0534.4331.0133.8038.5230.0324.7225.1327.3729.3025.1632.0922.1817.4318.6428.9028.1327.4532.6923.2629.0931.0326.9831.2634.92

HHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH

CONCCOCNCCOCCSCNCCOCONCCOCCCCNCCCCCNCCOCCCNCC

193219331934193519361937193819391940194119421943194419451946194719481949195019511952195319541955195619571958195919601961196219631964196519661967196819691970197119721973197419751976

OCBCGCDNECZNH1NH2NCACOCBCGCDOE1NE2NCACOCBOG1CG2NCACOCBCGCDNCACOCBCGCDOE1OE2NCACOCB

ARG HARG HARG HARG HARG HARG HARG HARG HGLN HGLN HGLN HGLN HGLN HGLN HGLN HGLN HGLN HTHR HTHR HTHR HTHR HTHR HTHR HTHR HPRO HPRO HPRO HPRO HPRO HPRO HPRO HGLU HGLU HGLU HGLU HGLU HGLU HGLU HGLU HGLU HLYS HLYS HLYS HLYS HLYS H

383838383838383839393939393939393940404040404040414141414141414242424242424242424343434343

1.539-1.218-0.548-1.297-0.684-1.174-2.288-0.5561.1612.5642.7682.0972.9024.3754.7184.0235.7983.6813.9514.7945.3384.7076.0564.0494.8915.6747.1197.8825.6094.4634.1247.4918.7798.7249.6279.1199.1677.7867.3237.1897.5717.4707.5697.9228.596

7.1005.6854.5053.2532.0820.8550.648-0.1557.2977.3946.3966.4428.8049.03810.50711.27610.9035.4684.4445.0346.1313.2783.6762.8674.3194.8535.0545.8373.8582.8903.1714.2574.4495.6535.9273.1721.9321.3240.7671.3946.3547.6587.5688.5238.534

13.01114.35713.73214.07813.47113.56814.25612.97115.23715.60016.71417.73916.07316.27316.38117.03915.74216.49817.48518.59618.46616.86016.59215.55219.72120.82620.38320.93821.98321.71320.17419.36718.72717.78817.00917.95318.85318.94517.95920.02017.85617.21015.69115.01017.748

36.4230.8232.2931.6145.3049.1444.2939.2934.3536.2132.9436.8635.4840.4630.9746.8739.1332.2126.9536.2733.9025.6030.9519.8143.3442.3340.4746.1746.0044.5437.3639.8439.6739.7238.2443.6959.1178.3271.1693.3637.8631.7830.8234.0630.63

HHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH

OCCCNCNNNCCOCCCONNCCOCOCNCCOCCCNCCOCCCOONCCOC

197719781979198019811982198319841985198619871988198919901991199219931994199519961997199819992000200120022003200420052006200720082009201020112012201320142015201620172018201920202021

CGCDCENZNCACOCBCGCDNECZNH1NH2NCACOCBCGCD1CD2NCACOCBCGCDOE1OE2NCACOCBCGCD1CD2NE1CE2CE3CZ2CZ3

LYS HLYS HLYS HLYS HARG HARG HARG HARG HARG HARG HARG HARG HARG HARG HARG HLEU HLEU HLEU HLEU HLEU HLEU HLEU HLEU HGLU HGLU HGLU HGLU HGLU HGLU HGLU HGLU HGLU HTRP HTRP HTRP HTRP HTRP HTRP HTRP HTRP HTRP HTRP HTRP HTRP HTRP H

434343434444444444444444444444454545454545454546464646464646464647474747474747474747474747

8.3309.24710.47410.0527.1567.0875.6404.7107.5749.0449.4569.90410.96611.98910.9955.4574.1313.6884.4614.1314.3924.8673.1312.4451.9240.508-0.4111.8742.8472.7851.6913.8440.327-1.012-1.886-1.548-0.885-2.202-3.297-2.617-4.364-3.948-1.989-4.609-2.651

8.97110.1139.6159.0646.4426.3236.5205.9534.9514.7013.3513.4394.1394.3224.6727.3157.5776.4886.0588.93810.15211.31010.5226.0385.0225.3745.4733.6383.3931.9431.4731.2695.5775.7514.5243.3935.9915.8416.7294.7546.3085.0253.5944.1422.710

19.18919.62720.39521.68015.12213.66813.20413.78713.19713.37912.80211.41211.00711.8329.78512.15011.59710.6119.76710.89811.79410.93812.59010.7259.8189.34410.15210.49611.66812.23112.63012.2808.0457.5007.7707.4435.9965.3415.4264.4814.6974.0784.0363.2403.200

45.4683.8296.1387.5829.4129.4633.4837.9831.5035.5856.9171.8770.5272.5965.1230.8123.6228.2426.2018.0019.8824.5414.9728.3826.3226.5833.1435.2149.1864.8167.3852.2130.5725.4830.8732.2625.2523.7536.8423.0839.4127.4023.5216.4622.42

HHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH

CCCNNCCOCCCNCNNNCCOCCCCNCCOCCCOONCCOCCCCNCCCC

202220232024202520262027202820292030203120322033203420352036203720382039204020412042204320442045204620472048204920502051205220532054205520562057205820592060206120622063206420652066

CH2NCACOCBCG1CG2NCACOCBNCACOCBOGNCACOCBCG1CG2CD1NCACOCBOGNCACOCBOGNCACONCA

TRP HVAL HVAL HVAL HVAL HVAL HVAL HVAL HALA HALA HALA HALA HALA HSER HSER HSER HSER HSER HSER HILE HILE HILE HILE HILE HILE HILE HILE HSER HSER HSER HSER HSER HSER HSER HSER HSER HSER HSER HSER HGLY HGLY HGLY HGLY HGLY HGLY H

474848484848484849494949495050505050505151515151515151525252525252535353535353545454545555

-3.972-3.034-3.887-5.099-5.503-4.355-5.379-3.171-5.715-6.900-7.176-6.710-8.093-7.942-8.289-9.629-9.863-7.229-6.021-10.508-11.828-11.958-11.591-12.919-14.287-12.925-15.356-12.450-12.533-13.920-14.793-12.218-13.410-14.093-15.357-16.543-17.655-15.271-14.297-16.279-17.355-17.537-18.380-16.673-16.775

2.9864.7783.6713.4922.3863.9472.8963.9074.6324.5605.8896.9474.1815.8016.9626.7375.7037.2207.6787.7177.6468.8389.9667.6957.3799.0517.1928.6009.72510.3689.9989.2168.70111.39612.12111.19811.38413.21714.18410.1899.2968.1187.2508.0827.009

2.8038.4268.8447.9257.58610.27310.69811.2217.5556.7065.9966.3997.5854.9154.1133.4422.8203.0363.6043.5752.9782.0322.3804.0793.4794.7544.5100.828-0.096-0.0600.712-1.504-2.095-0.908-0.908-1.204-0.725-1.969-1.575-2.056-2.474-1.512-1.697-0.4790.505

27.7535.9332.9631.2934.8331.3145.3240.0732.5730.9731.4135.8927.7128.7031.2733.0133.7729.7736.8731.7330.2533.0235.6929.5426.9223.3838.1632.2937.7240.7335.2841.6245.1347.2550.6149.7553.9152.8358.4045.2453.1655.6361.2553.2254.51

HHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH

CNCCOCCCNCCOCNCCOCONCCOCCCCNCCOCONCCOCONCCONC

206720682069207020712072207320742075207620772078207920802081208220832084208520862087208820892090209120922093209420952096209720982099210021012102210321042105210621072108210921102111

CONCACOCBCGOD1ND2NCACOCBOG1CG2NCACOCBCGCD1CD2CE1CE2CZOHNCACOCBCGCD1CD2CE1CE2CZOHNCACO

GLY HGLY HASN HASN HASN HASN HASN HASN HASN HASN HTHR HTHR HTHR HTHR HTHR HTHR HTHR HTYR HTYR HTYR HTYR HTYR HTYR HTYR HTYR HTYR HTYR HTYR HTYR HTYR HTYR HTYR HTYR HTYR HTYR HTYR HTYR HTYR HTYR HTYR HTYR HPRO HPRO HPRO HPRO H

555556565656565656565757575757575758585858585858585858585859595959595959595959595960606060

-16.009-16.062-15.076-14.132-13.066-12.441-13.471-14.484-14.773-15.032-12.896-11.950-10.671-10.627-12.638-13.012-13.899-9.590-8.307-7.600-7.653-7.448-8.165-9.022-7.996-9.688-8.664-9.510-10.205-6.923-6.228-4.923-4.744-7.114-8.483-8.692-9.578-9.949-10.839-11.018-12.274-3.983-2.717-3.021-3.990

5.7604.7105.8664.7754.7335.7294.9734.7285.5913.5013.5343.4012.6721.9592.6311.3353.3792.9062.3022.0132.8163.2463.8564.9373.3505.4973.9044.9795.5370.8710.448-0.272-0.877-0.5210.0010.811-0.3511.2480.0870.8831.296-0.209-0.912-2.380-2.667

0.0620.688-0.905-1.117-0.0200.321-2.482-3.571-4.395-3.5700.5681.6701.2480.2542.8012.3293.2511.9781.6532.9623.8880.803-0.374-0.200-1.661-1.265-2.737-2.531-3.5823.0234.2293.9562.9104.9905.3086.4104.5316.7384.8515.9616.3254.9014.6915.0395.748

55.0363.6150.2053.1851.9752.3761.7770.1679.1983.8148.6140.9238.3140.6740.8342.1123.8540.2138.4737.2639.7837.9445.0038.6942.2848.5645.8250.9945.0538.1536.2335.9741.6632.9233.0526.1621.8828.2030.6627.8247.4942.0742.4742.1234.35

HHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH

CONCCOCCONNCCOCOCNCCOCCCCCCCONCCOCCCCCCCONCCO

211221132114211521162117211821192120212121222123212421252126212721282129213021312132213321342135213621372138213921402141214221432144214521462147214821492150215121522153215421552156

CBCGCDNCACOCBCGOD1OD2NCACOCBOGNCACOCBCG1CG2NCACOCBCGCDCENZNCACONCACOCBCGCDNE

PRO HPRO HPRO HASP HASP HASP HASP HASP HASP HASP HASP HSER HSER HSER HSER HSER HSER HVAL HVAL HVAL HVAL HVAL HVAL HVAL HLYS HLYS HLYS HLYS HLYS HLYS HLYS HLYS HLYS HGLY HGLY HGLY HGLY HARG HARG HARG HARG HARG HARG HARG HARG H

606060616161616161616162626262626263636363636363646464646464646464656565656666666666666666

-1.787-2.423-3.881-2.213-2.466-2.319-2.773-1.467-1.512-2.632-0.421-1.672-1.359-2.619-2.612-0.589-0.528-3.723-4.947-6.183-7.301-5.128-3.887-5.337-5.959-7.068-7.836-7.266-6.501-7.097-6.884-5.402-4.916-9.165-10.047-10.249-11.115-9.381-9.459-9.991-10.440-8.054-7.998-6.616-5.577

-0.2820.9980.718-3.314-4.702-4.842-5.818-5.625-5.513-5.429-5.524-3.849-3.808-3.866-4.355-2.516-2.299-3.309-3.243-3.685-3.711-1.800-1.349-0.882-4.004-4.431-5.603-6.604-4.839-4.021-4.688-4.805-3.520-5.387-6.409-6.226-6.832-5.381-5.142-3.739-3.458-5.306-6.360-7.012-6.084

5.7286.0706.0394.5564.9046.4157.0064.2192.7222.1612.1107.0168.4389.30910.4318.71810.1278.7709.5628.7709.26710.03910.8098.8497.4826.6367.2547.6665.2754.1282.7682.3981.8997.2957.8459.3519.9719.94211.38011.70312.80611.96013.06513.16012.704

37.6838.5541.2346.3353.5052.8060.2456.5372.0770.7191.2152.9748.8149.1348.2850.5560.8245.5739.3037.7537.5242.3934.9031.9740.8847.2947.6846.1149.6459.2571.5681.5349.4447.2842.1842.8350.9543.9644.0543.6249.6546.9435.4836.4643.95

HHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH

CCCNCCOCCOONCCOCONCCOCCCNCCOCCCCNNCCONCCOCCCN

215721582159216021612162216321642165216621672168216921702171217221732174217521762177217821792180218121822183218421852186218721882189219021912192219321942195219621972198219922002201

CZNH1NH2NCACOCBCGCD1CD2CE1CE2CZNCACOCBOG1CG2NCACOCBCG1CG2CD1NCACOCBOGNCACOCBCGCDNECZNH1

ARG HARG HARG HPHE HPHE HPHE HPHE HPHE HPHE HPHE HPHE HPHE HPHE HPHE HTHR HTHR HTHR HTHR HTHR HTHR HTHR HILE HILE HILE HILE HILE HILE HILE HILE HSER HSER HSER HSER HSER HSER HARG HARG HARG HARG HARG HARG HARG HARG HARG HARG H

666666676767676767676767676768686868686868696969696969696970707070707071717171717171717171

-5.142-5.650-4.169-9.864-10.226-11.197-11.115-8.972-8.052-7.966-7.234-7.074-6.344-6.263-12.103-12.990-13.142-13.517-14.353-14.194-15.300-12.783-12.986-14.365-14.922-11.907-12.088-12.050-10.819-14.928-16.200-16.299-15.622-17.325-17.077-17.245-17.510-18.987-19.806-16.894-17.360-16.570-16.406-15.497-14.654

-5.162-5.116-4.317-2.799-1.396-0.910-1.327-0.505-0.631-1.8030.428-1.9160.327-0.847-0.0150.4901.9912.515-0.178-1.5950.2712.6954.1334.4943.8434.7726.2954.2637.0415.5566.0737.5618.0765.3105.3128.1719.5859.9009.24010.3569.86010.49911.92512.70312.209

13.58414.80213.22910.77310.9999.9198.75510.93212.10112.82612.45713.89013.51214.23110.2949.2669.40010.4419.4389.3568.3198.3178.3107.7636.8877.4417.4265.9967.8378.3567.8828.1999.0798.5889.9957.5007.6797.7647.1426.5085.1474.0494.3193.7392.838

50.1343.6044.3944.7740.2141.9840.8535.5834.0846.6534.3547.2628.1236.8936.9839.6037.7033.5638.6938.2040.0535.2233.3929.1235.8827.0528.3539.6619.7030.0132.1336.0141.3825.5741.9935.8434.2733.2236.6631.2224.6424.1139.1313.5121.43

HHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH

CNNNCCOCCCCCCCNCCOCOCNCCOCCCCNCCOCONCCOCCCNCN

220222032204220522062207220822092210221122122213221422152216221722182219222022212222222322242225222622272228222922302231223222332234223522362237223822392240224122422243224422452246

NH2NCACOCBCGOD1OD2NCACOCBCGOD1ND2NCACOCBNCACOCBCGCDNECZNH1NH2NCACOCBCGOD1ND2NCACO

ARG HASP HASP HASP HASP HASP HASP HASP HASP HASN HASN HASN HASN HASN HASN HASN HASN HALA HALA HALA HALA HALA HARG HARG HARG HARG HARG HARG HARG HARG HARG HARG HARG HASN HASN HASN HASN HASN HASN HASN HASN HILE HILE HILE HILE H

717272727272727272737373737373737374747474747575757575757575757575767676767676767677777777

-15.416-19.324-20.700-20.669-20.260-21.150-22.622-23.145-23.257-21.077-21.075-22.025-21.655-21.341-20.148-19.034-20.369-23.246-24.205-23.633-23.592-25.509-23.173-22.618-21.177-20.691-22.701-24.098-24.062-23.498-23.312-22.787-23.647-20.504-19.094-18.212-17.391-18.884-19.332-18.695-20.423-18.390-17.600-16.944-17.548

13.97210.90711.35512.79013.72411.34211.67712.52211.10312.95014.25215.26116.41914.09813.53413.56713.02714.83715.74716.27517.48415.03815.36415.75916.23116.83514.60714.28713.29513.90513.27213.92911.98815.96416.33415.58416.18417.83418.64219.63018.22114.27213.47612.34011.725

4.0908.5568.6768.1418.84210.12910.2849.51811.1946.8846.2376.8377.0344.7484.0174.5232.8177.1357.7369.0469.2757.9889.90011.19011.11912.07212.20112.70913.87315.07416.23217.26816.3579.9999.82910.82311.51610.0308.8478.4748.23110.89811.80411.05010.174

32.6137.5437.7436.7029.7541.5748.1949.9756.2936.0034.2338.0642.9835.9428.6738.3040.6940.2139.7043.0544.6042.5143.4940.9037.7533.2645.0361.3760.1078.9484.6658.2580.6335.2233.9736.0735.7432.3538.6645.8048.9636.7132.4635.6435.33

HHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH

NNCCOCCOONCCOCCONNCCOCNCCOCCCNCNNNCCOCCONNCCO

224722482249225022512252225322542255225622572258225922602261226222632264226522662267226822692270227122722273227422752276227722782279228022812282228322842285228622872288228922902291

CBCG1CG2CD1NCACOCBCGCD1CD2NCACOCBCGCD1CD2CE1CE2CZOHNCACOCBCGCD1CD2NCACOCBCGCDOE1NE2NCACO

ILE HILE HILE HILE HLEU HLEU HLEU HLEU HLEU HLEU HLEU HLEU HTYR HTYR HTYR HTYR HTYR HTYR HTYR HTYR HTYR HTYR HTYR HTYR HLEU HLEU HLEU HLEU HLEU HLEU HLEU HLEU HGLN HGLN HGLN HGLN HGLN HGLN HGLN HGLN HGLN HMET HMET HMET HMET H

777777777878787878787878797979797979797979797979808080808080808081818181818181818182828282

-18.464-19.212-17.578-20.069-15.692-14.882-14.783-14.611-13.486-12.471-12.957-11.163-14.885-14.814-13.764-13.455-16.155-17.303-17.389-18.290-18.426-19.333-19.401-20.456-13.221-12.272-12.681-12.510-10.833-9.905-10.141-8.445-13.261-13.588-12.477-11.955-14.898-15.181-16.017-16.772-15.848-12.046-10.916-11.369-12.060

12.90114.03812.17013.58612.07911.0209.91010.18711.57510.68810.31411.4148.6587.5396.5046.2586.8037.6368.0388.0478.8308.8419.23010.0145.8974.8163.7193.8615.2484.0663.6844.3962.6411.5860.5890.2950.949-0.381-0.1280.824-1.0480.146-0.759-2.034-1.982

12.94613.65113.96214.81311.40610.80611.85413.03910.4789.7658.4049.67311.42612.36412.03110.86412.42812.91014.23612.03014.66812.45313.76914.18113.07612.91113.88915.10013.20212.85011.39613.09613.36814.26814.17613.10813.80414.50415.73715.84216.70715.35015.46216.17117.192

40.8344.3240.4046.9440.6237.2036.2541.8130.3114.9028.7631.6335.1029.3029.9132.2628.9537.1319.8136.5044.5535.5940.1844.0432.7833.3739.1142.2727.3229.8929.2321.8737.5835.4235.7538.9732.2246.9963.7373.2254.6038.8938.0041.1042.49

HHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH

CCCCNCCOCCCCNCCOCCCCCCCONCCOCCCCNCCOCCCONNCCO

229222932294229522962297229822992300230123022303230423052306230723082309231023112312231323142315231623172318231923202321232223232324232523262327232823292330233123322333233423352336

CBCGSDCENCACOCBOGNCACOCBOGNCACOCBCGCD1CD2NCACOCBCGCDNECZNH1NH2NCACOCBOGNCACO

MET HMET HMET HMET HSER HSER HSER HSER HSER HSER HSER HSER HSER HSER HSER HSER HLEU HLEU HLEU HLEU HLEU HLEU HLEU HLEU HARG HARG HARG HARG HARG HARG HARG HARG HARG HARG HARG HSER HSER HSER HSER HSER HSER HGLU HGLU HGLU HGLU H

8282828282A82A82A82A82A82A82B82B82B82B82B82B82C82C82C82C82C82C82C82C838383838383838383838384848484848485858585

-9.786-9.219-7.917-8.890-10.994-11.395-10.238-9.323-12.561-12.101-10.293-9.247-7.940-6.946-9.129-10.320-7.934-6.730-5.498-5.581-7.032-7.982-8.308-7.340-4.354-3.055-2.213-2.434-2.359-3.236-2.544-3.470-3.033-1.820-3.825-1.201-0.3760.2600.6460.7590.2020.3781.0980.2190.678

-0.0791.1701.9922.540-3.182-4.446-5.431-5.335-5.052-5.716-6.381-7.383-6.652-6.935-8.213-8.914-5.717-4.932-5.720-6.625-3.824-2.753-1.699-2.116-5.361-5.936-4.938-3.735-6.300-7.145-7.435-8.063-8.224-7.821-8.810-5.519-4.674-3.585-2.511-5.531-6.382-3.916-3.027-1.927-1.027

16.23615.55416.52217.88815.62116.21416.24215.43115.42814.25817.17317.30417.53516.86616.01815.72118.48018.73919.17119.99219.75619.19420.24317.96918.59018.89519.69419.66317.57716.64615.30414.34913.08312.74112.17720.36121.20120.33220.77421.81722.81719.03118.12117.52116.823

40.9240.9543.0136.8639.3542.1243.1441.7942.5050.1840.7445.6544.3351.7844.4753.6040.3744.2342.9148.4047.8348.9142.5041.9640.8036.3735.9947.5736.6940.1634.8958.8364.1974.9364.5041.5446.1543.6047.1441.3161.1445.7844.0241.3747.91

HHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH

CCSCNCCOCONCCOCONCCOCCCCNCCOCCCNCNNNCCOCONCCO

233723382339234023412342234323442345234623472348234923502351235223532354235523562357235823592360236123622363236423652366236723682369237023712372237323742375237623772378237923802381

CBCGCDOE1OE2NCACOCBCGOD1OD2NCACOCBOG1CG2NCACOCBNCACOCBCGSDCENCACOCBCGCD1CD2CE1CE2CZOH

GLU HGLU HGLU HGLU HGLU HASP HASP HASP HASP HASP HASP HASP HASP HTHR HTHR HTHR HTHR HTHR HTHR HTHR HALA HALA HALA HALA HALA HMET HMET HMET HMET HMET HMET HMET HMET HTYR HTYR HTYR HTYR HTYR HTYR HTYR HTYR HTYR HTYR HTYR HTYR H

858585858586868686868686868787878787878788888888888989898989898989909090909090909090909090

1.7091.9440.9510.5000.597-1.099-1.967-1.996-2.856-3.369-3.287-2.847-3.632-1.010-0.869-0.1161.070-0.080-0.724-0.022-0.856-0.225-1.188-2.3680.252-0.652-1.458-2.140-1.489-0.571-1.307-2.161-0.855-3.453-4.190-4.611-5.294-5.408-5.038-4.360-5.308-3.957-4.910-4.235-3.826

-3.873-5.318-6.200-7.173-5.873-2.034-0.9350.1411.008-1.484-2.541-2.199-3.6900.0210.9952.2362.2020.324-0.8991.2423.3564.5815.7695.6364.3436.9538.1558.1177.9009.38310.71911.14411.1008.2958.2749.68310.4017.3495.8945.2565.1703.9403.8533.2441.944

17.00617.43816.72817.31815.59917.76717.37318.46118.51617.11116.02014.92116.28319.37520.44819.96519.66021.57621.94022.80019.85819.38219.41819.71717.94919.13719.09617.73616.71319.19219.12820.64821.79717.72116.46416.03216.77616.58316.48717.52315.33717.41615.21516.25616.120

47.5666.2783.8892.6478.2034.9335.0431.7839.3831.1848.6155.8259.2828.1828.9825.0329.0332.6345.7228.8730.6928.1827.7130.0723.6928.1825.3123.3426.0519.0828.5835.9223.3724.8128.4735.6138.4226.3321.8321.3323.3413.2532.1632.3731.42

HHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH

CCCOONCCOCCOONCCOCOCNCCOCNCCOCCSCNCCOCCCCCCCO

238223832384238523862387238823892390239123922393239423952396239723982399240024012402240324042405240624072408240924102411241224132414241524162417241824192420242124222423242424252426

NCACOCBCGCD1CD2CE1CE2CZOHNCACOCBSGNCACOCBNCACOCBCGCDNECZNH1NH2NCACOCBCGCD1CD2NCAC

TYR HTYR HTYR HTYR HTYR HTYR HTYR HTYR HTYR HTYR HTYR HTYR HCYS HCYS HCYS HCYS HCYS HCYS HALA HALA HALA HALA HALA HARG HARG HARG HARG HARG HARG HARG HARG HARG HARG HARG HLEU HLEU HLEU HLEU HLEU HLEU HLEU HLEU HASP HASP HASP H

919191919191919191919191929292929292939393939394949494949494949494949595959595959595969696

-4.199-4.482-5.437-5.311-3.190-2.193-2.378-1.057-1.471-0.149-0.3650.536-6.396-7.249-6.598-6.025-8.737-9.256-6.644-6.063-6.899-7.472-4.640-6.987-7.718-6.723-5.586-8.105-9.146-9.449-8.508-8.502-9.380-7.626-7.134-6.369-6.686-7.687-6.703-5.882-4.381-6.265-5.805-5.991-5.736

10.06311.38611.42310.60712.02612.37813.49311.60113.82111.92913.03913.37512.35212.51413.62414.57512.86014.09113.47414.46414.62013.65414.06615.85316.11215.77116.24417.58317.90519.38720.14921.47622.18922.08914.92214.53415.42915.27513.07712.53912.51211.11116.42317.31516.588

14.82114.27713.10512.19313.78114.84815.65315.04916.61616.01116.79017.76313.12011.94111.12011.66112.24513.5079.8108.9427.6927.1788.5737.2145.9934.8854.9025.9244.8804.8834.0683.9864.6713.2083.9492.7711.5710.8852.4381.2631.5640.8721.3560.218-1.105

29.6727.6830.6130.0625.8236.8730.7624.8721.5420.3419.9838.1234.7239.1031.3825.5335.3369.1522.9023.1431.5237.1722.9831.2227.8830.2135.0626.5632.0629.0743.5630.8332.8026.7428.9729.4234.0743.1231.8117.9233.1443.3833.3826.8728.04

HHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH

NCCOCCCCCCCONCCOCSNCCOCNCCOCCCNCNNNCCOCCCCNCC

242724282429243024312432243324342435243624372438243924402441244224432444244524462447244824492450245124522453245424552456245724582459246024612462246324642465246624672468246924702471

OCBCGOD1OD2NCACONCACOCBCGCD1CD2CE1CE2CZOHNCACOCBCGCD1CD2CE1CE2CZOHNCACOCBCGCD1CD2CE1CE2CZN

ASP HASP HASP HASP HASP HGLY HGLY HGLY HGLY HTYR HTYR HTYR HTYR HTYR HTYR HTYR HTYR HTYR HTYR HTYR HTYR HTYR HTYR HTYR HTYR HTYR HTYR HTYR HTYR HTYR HTYR HTYR HTYR HPHE HPHE HPHE HPHE HPHE HPHE HPHE HPHE HPHE HPHE HPHE HGLY H

969696969697979797989898989898989898989898999999999999999999999999100100100100100100100100100100100100A

-5.942-5.021-5.550-6.142-5.368-5.233-4.929-3.509-2.829-3.080-1.726-0.7320.479-1.735-2.226-1.549-3.278-1.902-3.636-2.954-3.289-1.290-0.4390.0771.129-1.259-1.157-2.191-0.026-2.0900.070-0.958-0.889-0.868-0.843-0.564-0.409-2.152-2.589-1.920-3.604-2.256-3.942-3.272-0.513

17.11218.48919.44918.96720.65515.34514.56613.99514.03013.41412.87313.89913.71811.61611.93612.86911.20613.05111.39512.31312.48714.99316.05616.95817.57616.88216.29116.47415.56515.94615.02815.21114.64816.95817.91217.52818.41418.70219.00219.95818.26420.16018.46419.40716.243

-2.1910.3671.4252.3921.276-0.982-2.178-2.126-1.109-3.264-3.319-3.869-3.839-4.192-5.559-6.342-6.116-7.672-7.442-8.218-9.547-4.421-4.942-3.819-3.918-5.933-7.294-8.208-7.666-9.487-8.941-9.847-11.107-2.882-1.771-0.3130.510-1.836-3.244-4.007-3.841-5.326-5.164-5.9060.023

31.1020.2835.2343.8234.5535.2134.9836.6055.1831.3336.6038.1138.3133.7138.4860.1958.1761.0766.4962.6351.3234.5728.1130.0645.1735.3045.2550.1967.3261.6966.7861.5364.8728.3633.0832.5128.9335.0740.1942.9832.6538.5522.6134.0832.84

HHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH

OCCOONCCONCCOCCCCCCCONCCOCCCCCCCONCCOCCCCCCCN

247224732474247524762477247824792480248124822483248424852486248724882489249024912492249324942495249624972498249925002501250225032504250525062507250825092510251125122513251425152516

CACONCACOCBCGCD1CD2CE1CE2CZNCACOCBNCACOCBCGCD1CD2CE1CE2CZOHNCACOCBCGCD1CD2NE1CE2CE3CZ2CZ3CH2

GLY HGLY HGLY HPHE HPHE HPHE HPHE HPHE HPHE HPHE HPHE HPHE HPHE HPHE HALA HALA HALA HALA HALA HTYR HTYR HTYR HTYR HTYR HTYR HTYR HTYR HTYR HTYR HTYR HTYR HTRP HTRP HTRP HTRP HTRP HTRP HTRP HTRP HTRP HTRP HTRP HTRP HTRP HTRP H

100A100A100A100B100B100B100B100B100B100B100B100B100B100B101101101101101102102102102102102102102102102102102103103103103103103103103103103103103103103

-0.246-1.375-2.508-1.062-2.009-1.848-0.932-1.681-1.841-0.723-3.104-0.864-3.252-2.136-2.758-2.760-3.142-2.666-3.625-4.008-4.398-4.423-4.814-5.769-5.724-5.415-5.923-5.306-5.812-5.504-5.400-3.981-3.950-4.657-4.653-2.504-1.662-1.428-0.956-0.630-0.330-0.7960.436-0.0270.574

15.85915.97716.39315.56515.64817.06717.35814.61713.18612.39112.64111.08911.32910.55617.93319.35519.78320.79020.07219.03819.41418.17417.10420.09821.48422.61021.66223.84322.89623.99025.24618.31917.21317.63518.81116.83916.41317.10715.17816.37415.18314.06514.12313.00313.039

1.4032.4332.1473.6564.7565.2786.0455.8455.3945.1245.2114.6824.7664.5024.8335.1546.5707.0694.1507.2268.5749.4328.9688.5577.9388.7166.5658.1585.9956.7946.22210.67511.60812.88813.24911.94710.7909.63410.6658.7979.40311.4958.95611.0449.786

24.0731.8631.4331.6230.2328.5232.6735.3037.1128.9027.1929.0527.2031.1527.5625.6625.1936.4729.9127.8925.3224.3930.4223.3332.1828.4326.3110.3016.3634.6430.0824.2428.5530.1337.4028.9525.3818.6530.5821.5625.4728.4515.5524.5726.41

HHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH

CCONCCOCCCCCCCNCCOCNCCOCCCCCCCONCCOCCCCNCCCCC

251725182519252025212522252325242525252625272528252925302531253225332534253525362537253825392540254125422543254425452546254725482549255025512552255325542555255625572558255925602561

NCACONCACOCBCGCDOE1NE2NCACONCACOCBOG1CG2NCACOCBCGCD1CD2NCACOCBCG1CG2NCACOCBN

GLY HGLY HGLY HGLY HGLN HGLN HGLN HGLN HGLN HGLN HGLN HGLN HGLN HGLY HGLY HGLY HGLY HTHR HTHR HTHR HTHR HTHR HTHR HTHR HLEU HLEU HLEU HLEU HLEU HLEU HLEU HLEU HVAL HVAL HVAL HVAL HVAL HVAL HVAL HALA HALA HALA HALA HALA HVAL H

104104104104105105105105105105105105105106106106106107107107107107107107108108108108108108108108109109109109109109109110110110110110111

-5.268-5.920-4.886-3.728-5.304-4.403-4.074-3.222-5.011-6.191-7.414-8.035-7.770-4.755-4.490-5.137-5.420-5.384-6.034-5.319-5.018-7.494-8.205-7.572-5.026-4.162-4.918-5.874-3.419-1.902-1.186-1.292-4.448-4.950-3.831-2.822-5.504-5.974-6.670-4.054-3.117-3.807-4.881-2.478-3.181

16.67716.99316.81516.54616.93616.80915.37015.12417.47818.38418.04218.92616.75214.42013.02612.50813.25811.20910.4489.1248.34310.1809.7789.0438.9027.7896.4716.3588.1558.1199.1776.7675.4624.1073.1732.9803.6122.1694.4782.4951.4670.1320.0691.940-0.937

13.57314.82515.91715.61717.17318.31318.67319.52419.53619.22820.07020.68120.10518.05118.35419.63320.56719.66820.73621.00720.11720.36021.53319.33522.29922.65322.83623.59223.93623.75024.59624.12722.07722.26822.73322.06820.93521.08320.49423.85624.31124.54225.13525.62024.070

30.4923.2324.3326.4931.0530.9434.3141.9135.5152.1568.6761.1755.7332.5928.3328.8030.1029.4133.1433.8333.7930.9242.2832.3534.9339.4536.3740.3839.6520.0020.0020.0033.5238.5041.9545.6534.9336.2627.0341.7844.4542.4443.0744.0443.71

HHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH

NCCONCCOCCCONNCCONCCOCOCNCCOCCCCNCCOCCCNCCOCN

256225632564256525662567256825692570257125722573257425752576257725782579258025812582258325842585258625872588258925902591259225932594259525962597259825992600260126022603260426052606

CACOCBCG1CG2NCACOCBOGNCACOCBNCACOCBNCACOCBNCACOCBOG1CG2NCACOCBOG1CG2NCACO

VAL HVAL HVAL HVAL HVAL HVAL HSER HSER HSER HSER HSER HSER HALA HALA HALA HALA HALA HALA HALA HALA HALA HALA HALA HALA HALA HALA HALA HTHR HTHR HTHR HTHR HTHR HTHR HTHR HTHR HTHR HTHR HTHR HTHR HTHR HTHR HPRO HPRO HPRO HPRO H

111111111111111111112112112112112112113113113113113114114114114114115115115115115116116116116116116116117117117117117117117118118118118

-3.591-2.668-1.552-3.684-4.683-4.189-3.189-3.314-4.756-5.722-2.838-1.412-4.857-3.631-3.050-1.951-2.631-3.851-3.501-4.589-5.200-2.174-4.843-5.951-5.508-4.381-6.590-6.447-6.197-5.902-6.514-7.435-8.157-8.353-4.893-4.516-4.807-4.390-3.019-2.778-2.561-5.242-5.168-3.872-3.247

-2.301-3.122-3.511-2.843-3.970-1.718-3.346-3.814-4.215-3.626-2.698-2.761-5.297-5.952-5.274-4.735-5.866-5.290-4.512-3.481-2.905-3.801-3.279-2.416-0.977-0.703-3.008-0.0421.3601.5530.9552.1742.5411.3452.4012.6734.1285.0682.3811.0152.6164.8366.2966.7385.971

24.19525.09124.73722.79322.74121.89726.31627.69128.02427.56728.62128.73428.81429.24130.47630.47128.08531.55532.73533.03132.14532.46934.33334.71634.98635.37435.97334.72835.04536.53437.40834.65235.83233.75336.80338.18538.56937.90538.32537.97939.77139.02839.16639.85140.578

46.4148.7251.0046.0452.6736.7653.1860.0963.1162.2459.3968.3069.5864.0566.5767.6661.1774.5275.1873.1575.4581.1620.0020.0020.0020.0020.0048.1749.9153.5461.7651.9759.7567.3355.7152.9652.3354.2454.8157.2168.9653.9850.3951.7652.75

HHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH

CCOCCCNCCOCONCCOCNCCOCNCCOCNCCOCOCNCCOCOCNCCO

260726082609261026112612261326142615261626172618261926202621262226232624262526262627262826292630263126322633263426352636263726382639264026412642264326442645264626472648264926502651

CBCGCDNCACOCBCGCDNCACOCBOGNCACOCBCG1CG2NCACOCBCGCD1CD2CE1CE2CZOHNCACOCBCGCDNCAC

PRO HPRO HPRO HPRO HPRO HPRO HPRO HPRO HPRO HPRO HSER HSER HSER HSER HSER HSER HVAL HVAL HVAL HVAL HVAL HVAL HVAL HTYR HTYR HTYR HTYR HTYR HTYR HTYR HTYR HTYR HTYR HTYR HTYR HPRO HPRO HPRO HPRO HPRO HPRO HPRO HLEU HLEU HLEU H

118118118119119119119119119119120120120120120120121121121121121121121122122122122122122122122122122122122123123123123123123123124124124

-6.392-6.424-6.187-3.460-2.234-2.362-3.462-1.824-3.141-3.998-1.206-0.984-0.1500.994-0.264-1.175-0.788-0.1210.459-0.246-1.141-0.418-2.0521.8032.4823.0433.5663.6223.0842.0843.5661.5603.0492.0551.5472.9443.4534.9605.5142.6832.5642.2015.6267.0667.407

6.6115.4524.2777.9928.5189.0929.2389.59010.1788.9439.41010.06211.33111.3139.0758.04912.47013.74914.31514.71714.72715.85614.00214.29814.86716.25616.51213.92412.56112.38111.46211.11810.19710.0228.76317.16818.53618.60617.91719.27118.22616.98619.43219.57520.984

40.00440.93540.01039.63440.23141.64042.17739.23738.87938.64542.22043.50543.34242.91144.42744.82943.66743.46044.75845.67742.87242.14041.89844.82245.97845.66344.58746.37246.63247.58345.92147.81646.16047.10647.35946.63446.51346.72047.58147.59548.66747.89345.92346.03846.455

53.0753.5756.1550.7751.9957.3260.8547.6145.2453.3357.5952.7150.8955.2556.4163.4548.3845.0947.5250.7442.4841.6138.2848.8846.6249.8752.3242.1339.1433.2726.4439.6241.3139.3546.8349.8348.2150.8655.8952.9751.6243.8049.8352.2748.73

HHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH

CCCNCCOCCCNCCOCONCCOCCCNCCOCCCCCCCONCCOCCCNCC

265226532654265526562657265826592660266126622663266426652666266726682669267026712672267326742675267626772678267926802681268226832684268526862687268826892690269126922693269426952696

OCBCGCD1CD2NCACOCBNCACOCBCGCDOXTNCACOCBOG1CG2NCACOCBCGOD1ND2NCACOCBOGNCACOCBCG

LEU HLEU HLEU HLEU HLEU HALA HALA HALA HALA HALA HPRO HPRO HPRO HPRO HPRO HPRO HPRO HPRO HTHR HTHR HTHR HTHR HTHR HTHR HTHR HASN HASN HASN HASN HASN HASN HASN HASN HSER HSER HSER HSER HSER HSER HMET HMET HMET HMET HMET HMET H

124124124124124125125125125125126126126126126126126126132132132132132132132133133133133133133133133134134134134134134135135135135135135

7.3807.7677.6718.3328.3267.7178.0809.55110.0947.24110.22111.63911.83410.80811.98510.6949.70512.99716.84515.83516.09115.68314.47214.44614.25016.82817.28117.04517.64618.78719.06318.74919.65016.08615.90114.78214.09217.22517.39114.68113.64013.23413.83714.15813.679

21.91519.22417.77217.62816.84021.11822.38922.35321.29522.63123.51423.57423.15423.01825.04025.72724.85822.97430.32330.84532.32233.22830.67931.46129.21432.54833.90234.26733.71633.95834.98334.80136.11135.20335.78835.12335.76735.72936.93633.75833.00731.73731.39332.61933.454

45.64844.71544.21242.85345.21247.73948.33748.71049.01749.58048.67649.02750.47551.17548.80349.09148.37050.89449.32648.41648.09448.81549.08950.28349.46646.98146.66645.19544.28346.96848.03949.21247.60244.97943.64942.82842.04842.88842.14242.95042.21442.97744.03740.82739.620

48.2056.1553.0148.3959.8950.0152.8554.6252.8558.2953.3554.5356.2761.5353.6660.5348.2262.11131.55132.47130.65132.1532.60134.97131.87126.17123.00118.12118.63124.75125.18130.25119.92109.67100.8295.3896.71102.4092.2685.9775.4568.6667.1178.1687.38

HHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH

OCCCCNCCOCNCCOCCCONCCOCOCNCCOCCONNCCOCONCCOCC

269726982699270027012702270327042705270627072708270927102711271227132714271527162717271827192720272127222723272427252726272727282729273027312732273327342735273627372738273927402741

SDCENCACOCBCG1CG2NCACOCBOG1CG2NCACOCBCGCD1CD2NCACONCACOCBSGNCACOCBCGCD1CD2NCAC

MET HMET HVAL HVAL HVAL HVAL HVAL HVAL HVAL HTHR HTHR HTHR HTHR HTHR HTHR HTHR HLEU HLEU HLEU HLEU HLEU HLEU HLEU HLEU HGLY HGLY HGLY HGLY HCYS HCYS HCYS HCYS HCYS HCYS HLEU HLEU HLEU HLEU HLEU HLEU HLEU HLEU HVAL HVAL HVAL H

135135136136136136136136136137137137137137137137138138138138138138138138139139139139140140140140140140141141141141141141141141142142142

11.91211.76412.39611.86211.45010.79410.64910.01711.09211.81711.26510.46410.98012.35812.94211.7729.1958.3508.0278.2607.0717.3135.9967.9447.4987.1975.9595.2975.6634.5034.9405.6333.3771.7044.5484.9103.6462.8825.7356.2887.2597.0023.4402.2912.758

33.39333.47330.92429.78728.65528.88130.19428.97231.16427.44426.33325.39924.86725.49226.22924.20125.21924.31823.18423.29425.01626.15526.84825.61122.09120.97420.19520.46719.20518.35116.92516.69818.81318.27615.96914.58013.73413.52314.05512.63112.57012.23713.26812.45010.999

39.42537.63842.57643.31242.38341.36944.18544.81345.26242.60741.84242.73543.71441.16540.08740.63742.40443.16242.22041.01243.62244.61344.93445.87042.75341.88742.24443.23541.41441.59241.24740.25040.65541.14142.08141.85041.66242.60143.03142.94541.78444.23240.43240.06839.994

112.3195.0966.5364.3860.8660.5263.7166.5270.9760.7855.8952.8551.8354.0948.5857.4950.9151.8849.9553.0850.5346.8862.8875.2947.4746.5147.5348.1852.1354.8349.4044.9957.1076.4746.3042.1240.1739.8046.5152.0155.6152.2338.3737.8143.46

HHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH

SCNCCOCCCNCCOCOCNCCOCCCCNCCONCCOCSNCCOCCCCNCC

274227432744274527462747274827492750275127522753275427552756275727582759276027612762276327642765276627672768276927702771277227732774277527762777277827792780278127822783278427852786

OCBCC1CG2NCACOCBCGCDCENZNCACONCACOCBCGCD1CD2CE1CE2CZOHNCACOCBCGCD1CD2CE1CE2CZNCACOCB

VAL HVAL HVAL HVAL HLYS HLYS HLYS HLYS HLYS HLYS HLYS HLYS HLYS HGLY HGLY HGLY HGLY HTYR HTYR HTYR HTYR HTYR HTYR HTYR HTYR HTYR HTYR HTYR HTYR HPHE HPHE HPHE HPHE HPHE HPHE HPHE HPHE HPHE HPHE HPHE HPRO HPRO HPRO HPRO HPRO H

142142142142143143143143143143143143143144144144144145145145145145145145145145145145145146146146146146146146146146146146147147147147147

3.1681.7290.6611.1492.6843.1632.1411.0273.9394.9635.7436.9936.6932.5491.7040.369-0.5600.283-0.942-0.8200.277-1.302-0.3360.721-0.5011.5860.3581.3992.232-1.963-2.002-3.418-4.387-1.600-1.391-2.463-0.119-2.2660.080-0.995-3.554-2.444-2.207-2.689-2.986

10.52212.88911.91314.28310.2928.9207.7987.8348.7117.5827.5006.6535.2806.7915.6405.8826.4225.4825.5994.8494.6237.0627.8078.5227.8279.2468.5439.25810.0204.4543.7183.7933.7172.2661.4680.9081.2880.1880.5670.0193.9944.1515.6306.4563.507

38.93538.69538.22138.79941.11841.16740.99941.54942.46742.41343.72043.58943.09040.23339.98839.29939.89038.03737.25935.93035.41837.00236.12136.67034.74035.87133.93434.50633.71635.38534.13333.57934.32434.38733.13932.46332.62531.30531.46030.80432.26231.32531.12331.89830.068

44.3537.9034.1329.3745.1641.4846.3045.3443.2041.9942.2452.6567.3147.6252.5855.8263.6552.9646.9644.5243.1441.2454.1852.1237.2848.2345.8253.3751.9647.5240.6638.1337.8032.6540.8241.9938.8239.3432.2928.8241.7039.6541.9939.1741.33

HHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH

OCCCNCCOCCCCNNCCONCCOCCCCCCCONCCOCCCCCCCNCCOC

278727882789279027912792279327942795279627972798279928002801280228032804280528062807280828092810281128122813281428152816281728182819282028212822282328242825282628272828282928302831

CGCDNCACOCBCGCDOE1OE2NCACOCBCGCDNCACOCBCG1CG2NCACOCBOG1CG2NCACOCBCG1CG2NCACOCBOG1

PRO HPRO HGLU HGLU HGLU HGLU HGLU HGLU HGLU HGLU HGLU HPRO HPRO HPRO HPRO HPRO HPRO HPRO HVAL HVAL HVAL HVAL HVAL HVAL HVAL HTHR HTHR HTHR HTHR HTHR HTHR HTHR HVAL HVAL HVAL HVAL HVAL HVAL HVAL HTHR HTHR HTHR HTHR HTHR HTHR H

147147148148148148148148148148148149149149149149149149150150150150150150150151151151151151151151152152152152152152152153153153153153153

-4.403-4.829-1.459-1.200-2.481-3.292-0.0211.3421.9141.2683.021-2.698-1.771-2.349-3.262-1.760-3.227-3.673-1.797-2.239-1.769-0.866-1.528-2.023-0.022-2.457-2.050-1.853-2.467-3.167-4.169-3.814-0.916-0.653-0.5560.0440.6720.6131.840-1.249-1.215-0.947-1.146-2.589-3.610

4.0143.8575.9617.3527.8146.9937.4647.2868.5939.2408.9779.13110.12710.71210.15511.14811.2419.77511.84512.61713.97514.11112.17210.81012.13314.98516.34317.09416.80117.04117.49716.08218.05218.89020.33820.67018.46517.01318.63121.20322.63023.37722.86223.06122.721

30.07731.53030.08029.77029.10328.68328.80929.47330.01830.87229.58429.01829.53330.80831.41028.42428.13328.11831.19932.33631.97631.16633.63834.12933.44232.49332.17933.46734.48031.38932.30030.39033.41734.57634.13233.12135.23635.71434.27534.88734.59435.88036.97134.04834.987

36.4545.6140.4942.7748.7356.8241.7344.1054.5449.7448.0948.9346.0646.5452.0247.5935.2946.5346.4848.3651.5349.4846.5552.3545.3453.8752.7953.8758.7149.6868.4350.5754.8452.9552.6350.4851.8646.3453.5753.7756.8559.6060.7158.0963.79

HHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH

CCNCCOCCCOONCCOCCCNCCOCCCNCCOCOCNCCOCCCNCCOCO

283228332834283528362837283828392840284128422843284428452846284728482849285028512852285328542855285628572858285928602861286228632864286528662867286828692870287128722873287428752876

CG2NCACOCBCGCD1CD2NE1CE2CE3CZ2CZ3CH2NCACOCBCGOD1ND2NCACOCBOGNCACONCACOCBOGNCACOCBCG

THR HTRP HTRP HTRP HTRP HTRP HTRP HTRP HTRP HTRP HTRP HTRP HTRP HTRP HTRP HASN HASN HASN HASN HASN HASN HASN HASN HSER HSER HSER HSER HSER HSER HGLY HGLY HGLY HGLY HSER HSER HSER HSER HSER HSER HLEU HLEU HLEU HLEU HLEU HLEU H

153154154154154154154154154154154154154154154155155155155155155155155156156156156156156157157157157158158158158158158159159159159159159

-2.889-0.428-0.160-1.058-1.0901.3102.2202.8672.6063.6103.4572.3153.9882.8483.692-1.843-2.816-3.788-4.096-2.065-1.537-2.077-0.448-4.242-5.245-4.670-5.371-6.398-6.915-3.349-2.698-2.203-1.597-2.527-2.075-0.5480.060-2.678-2.0400.0691.5252.0212.0251.9931.795

22.37124.60725.38826.61727.43725.83924.70023.89224.18522.90923.06824.53322.35223.81122.70326.69827.77327.78028.80829.10329.31428.81430.09826.57026.48326.87526.97527.41727.04027.13827.49528.94529.43329.64731.02931.12032.13531.57830.96130.01529.95429.70428.59028.82229.147

32.71135.74336.94336.98536.07736.93637.22636.27638.52636.82738.28339.80239.32040.85640.61038.07538.18937.00636.41938.25539.65240.63439.73236.63135.57634.21233.21235.94937.22634.20132.94432.95232.00634.05834.21634.27333.95835.51336.63234.73434.67733.25232.74735.59337.075

53.3858.5659.0065.5168.4458.8363.2363.7955.0152.7853.6748.8247.9541.4346.1567.1870.5669.1071.2770.7670.0871.5364.3971.9271.4171.1574.0874.5775.7369.6867.4470.8667.8674.6082.2382.7885.8183.0199.7782.5282.3686.9979.5781.2879.39

HHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH

CNCCOCCCCNCCCCCNCCOCCONNCCOCONCCONCCOCONCCOCC

287728782879288028812882288328842885288628872888288928902891289228932894289528962897289828992900290129022903290429052906290729082909291029112912291329142915291629172918291929202921

CD1CD2NCACOCBOGNCACOCBOGNCACONCACOCBCG1CG2NCACOCBCGND1CD2CE1NE2NCACOCBOG1CG2NCAC

LEU HLEU HSER HSER HSER HSER HSER HSER HSER HSER HSER HSER HSER HSER HGLY HGLY HGLY HGLY HVAL HVAL HVAL HVAL HVAL HVAL HVAL HHIS HHIS HHIS HHIS HHIS HHIS HHIS HHIS HHIS HHIS HTHR HTHR HTHR HTHR HTHR HTHR HTHR HPHE HPHE HPHE H

159159160160160160160160161161161161161161162162162162163163163163163163163164164164164164164164164164164165165165165165165165166166166

2.5182.3132.4142.8163.9633.7823.2553.4095.1766.3567.0546.6347.3097.1938.1338.8738.5099.0247.5507.1597.6957.5975.6325.0495.1458.3218.8618.0497.97610.31311.18611.18512.12112.10012.6757.3706.6707.3997.4795.2544.5424.5118.0068.8438.045

28.15530.53530.80830.70429.70628.49532.08932.94830.26429.41129.31729.90030.00829.28328.51328.36927.07126.74726.33725.06023.88623.84725.00726.07723.64122.92621.76420.50220.03221.57722.59522.79123.46223.75424.17419.92818.68617.56017.48018.80519.81517.46616.71515.65214.422

37.98937.45532.58531.18531.00630.99330.70731.83730.81430.73432.09333.08329.70028.47532.13033.37934.10435.16533.51134.09333.26732.04834.14233.22233.69333.97333.27733.57834.70633.71733.02931.68733.60431.46132.59032.58032.81632.12830.90932.24332.96232.40832.97032.43832.045

93.6862.4593.6296.2392.9688.20102.1498.2289.7786.5677.9171.0592.3299.7669.9063.5659.4661.5856.4651.9146.1054.9956.3641.8437.0138.7338.2039.0245.9147.4150.3944.3255.5248.8154.0938.9434.5834.7036.9829.5426.8030.3733.4630.0234.42

HHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH

CCNCCOCONCCOCONCCONCCOCCCNCCOCCNCCNNCCOCOCNCC

292229232924292529262927292829292930293129322933293429352936293729382939294029412942294329442945294629472948294929502951295229532954295529562957295829592960296129622963296429652966

OCBCGCD1CD2CE1CE2CZNCACOCBCGCDNCACOCBNCACBCG1CG2ONCACOCBCGCD1CD2NCACOCBCGCDOE1OE2NCA

PHE HPHE HPHE HPHE HPHE HPHE HPHE HPHE HPRO HPRO HPRO HPRO HPRO HPRO HPRO HALA HALA HALA HALA HALA HVAL HVAL HVAL HVAL HVAL HVAL HLEU HLEU HLEU HLEU HLEU HLEU HLEU HLEU HGLU HGLU HGLU HGLU HGLU HGLU HGLU HGLU HGLU HSER HSER H

166166166166166166166166167167167167167167167168168168168168169169169169169169170170170170170170170170171171171171171171171171171172172

7.0179.85910.71511.91510.29512.68211.07212.2668.5397.9777.9368.8218.9109.5089.7206.8376.7007.5897.9785.2367.9518.7089.96010.74310.8457.1078.0297.2938.0999.2136.9665.9444.7175.4177.5098.1597.1976.0988.6269.93410.14611.2289.2167.6116.698

14.06815.25916.43216.63617.31617.74918.42918.65413.77712.55811.45011.34712.17513.50014.17410.6569.6588.4478.1659.2207.7466.5086.6095.2997.7425.3224.2092.9942.0721.6632.2731.1511.6140.5941.7870.876-0.2260.0291.6861.1591.7681.6132.391-1.486-2.576

32.60833.51633.87733.21034.85533.51235.14834.47831.00930.44531.50632.33529.30928.82630.26831.51832.56932.29131.16532.62333.38133.23934.11134.05533.62434.60932.87933.19634.11033.81331.88932.08432.87530.76135.28536.21736.66637.14037.42838.02139.38839.94039.89936.44936.764

40.7930.9223.8329.0231.7931.4524.7930.1439.2942.1347.7356.6645.0346.5934.5145.3342.8542.3439.5637.4241.7541.7245.0458.2743.3047.8947.2447.5750.5453.7149.5643.5047.6140.9155.6568.1467.7465.4172.4391.59120.67130.29122.9272.5078.89

HHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH

OCCCCCCCNCCOCCCNCCOCNCCCCONCCOCCCCNCCOCCCOONC

296729682969297029712972297329742975297629772978297929802981298229832984298529862987298829892990299129922993299429952996299729982999300030013002300330043005300630073008300930103011

COCBOGNCACOCBCGOD1OD2NCACOCBCGCD1CD2NCACOCBCGCD1CD2CE1CE2CZOHNCACOCBOG1CG2NCACOCBCG

SER HSER HSER HSER HASP HASP HASP HASP HASP HASP HASP HASP HLEU HLEU HLEU HLEU HLEU HLEU HLEU HLEU HTYR HTYR HTYR HTYR HTYR HTYR HTYR HTYR HTYR HTYR HTYR HTYR HTHR HTHR HTHR HTHR HTHR HTHR HTHR HLEU HLEU HLEU HLEU HLEU HLEU H

172172172172173173173173173173173173174174174174174174174174175175175175175175175175175175175175176176176176176176176177177177177177177

5.5645.3926.0994.7664.7393.6542.8661.6782.7482.3712.0702.3573.5862.9693.7985.0192.8191.7671.9410.3353.1503.8704.0253.2333.1563.1664.3461.9924.3541.9923.1713.1665.0585.3625.9216.9336.4686.2516.4805.2685.7836.0705.6894.7793.660

-2.629-3.582-2.293-1.804-1.563-1.391-0.1230.008-2.625-3.008-2.099-4.1930.8132.0593.2863.2552.0140.9930.5891.5124.4195.6316.6216.6376.3545.6315.4525.1054.7644.4184.2433.5097.4528.4999.6719.5288.0946.7549.04510.82211.98212.98812.79612.52613.499

35.73734.98638.14137.96835.78134.82435.15734.89334.85933.43032.65433.12035.79636.23235.81235.73437.76038.22239.68938.09135.54835.15036.28737.22633.99732.66731.95532.13730.75430.94830.25729.08936.17137.13936.35035.64538.13138.59239.31036.43935.74336.82037.96234.72935.078

79.7887.2179.7280.0774.9972.7865.4259.3581.6997.36108.23106.6463.5455.6551.4054.3354.6648.0853.1659.2343.1741.6840.7436.9347.7253.9851.2747.2258.2854.5055.8141.7541.7338.7341.8236.3341.0249.9936.3538.9933.7132.1732.1930.2931.11

HHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH

COCONCCOCCOONCCOCCCCNCCOCCCCCCCONCCOCOCNCCOCC

301230133014301530163017301830193020302130223023302430253026302730283029303030313032303330343035303630373038303930403041304230433044304530463047304830493050305130523053305430553056

CD1CD2NCACOCBOGNCACOCBOGNCACOCBOGNCACOCBCG1CG2NCACOCBOG1CG2NCAC0CBCG1CG2NCACO

LEU HLEU HSER HSER HSER HSER HSER HSER HSER HSER HSER HSER HSER HSER HSER HSER HSER HSER HSER HSER HVAL HVAL HVAL HVAL HVAL HVAL HVAL HTHR HTHR HTHR HTHR HTHR HTHR HTHR HVAL HVAL HVAL HVAL HVAL HVAL HVAL HPRO HPRO HPRO HPRO H

177177178178178178178178179179179179179179180180180180180180181181181181181181181182182182182182182182183183183183183183183184184184184

4.1862.8306.7517.1056.9947.2588.5348.6546.6006.4376.9536.6774.9514.8127.7708.3767.9337.7769.89310.3007.6927.3188.2128.4665.8625.7485.3658.7509.6388.9548.25910.94811.62111.8559.1618.5669.44910.2317.1996.2717.4039.32910.1429.8258.738

14.86713.65214.06015.06516.41616.53214.83115.14217.43718.73719.86219.92918.94819.93820.74021.80823.18923.45121.67922.19124.08025.44326.45826.37525.66125.67326.98527.41128.42729.78830.13428.52327.26429.59030.55531.88232.75532.25731.83430.83931.47534.08034.99034.72534.249

35.49833.83136.46337.44036.76135.56237.90639.27337.51136.87137.76738.95736.57335.55137.16137.94237.46036.27537.81336.54438.43838.08838.79639.99038.50140.02437.95138.04338.59938.58637.62937.79137.83138.36339.65339.79140.65041.45440.50839.82641.97140.49641.30042.76543.093

32.0537.8037.2936.2640.6237.7333.8353.7035.7436.8839.9743.9341.6641.4444.7747.1751.7356.6346.7039.6654.7952.0150.4747.1050.3847.1239.2848.3548.0851.6350.2647.8851.8129.1756.6657.1759.9059.5558.9361.7241.3566.4066.4967.2566.00

HHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH

CCNCCOCONCCOCONCCOCONCCOCCCNCCOCOCNCCOCCCNCCO

305730583059306030613062306330643065306630673068306930703071307230733074307530763077307830793080308130823083308430853086308730883089309030913092309330943095309630973098309931003101

CBCGCDNCACOCBOGNCACOCBOGNCACOCBCGCDNCACOCBCGCDNECZNH1NH2NCACOCBCGCDNCACOCB

PRO HPRO HPRO HSER HSER HSER HSER HSER HSER HSER HSER HSER HSER HSER HSER HPRO HPRO HPRO HPRO HPRO HPRO HPRO HARG HARG HARG HARG HARG HARG HARG HARG HARG HARG HARG HPRO HPRO HPRO HPRO HPRO HPRO HPRO HSER HSER HSER HSER HSER H

184184184185185185185185185186186186186186186187187187187187187187188188188188188188188188188188188189189189189189189189190190190190190

9.6739.3148.55210.77910.5869.3528.67311.82712.9939.0617.9046.6336.0167.7688.7106.2465.0514.7563.6485.3326.0296.9965.7455.5686.6497.7765.6804.6104.9566.3716.9416.2218.2396.3245.0214.0063.3075.4006.5247.3463.9152.9631.7190.7023.578

36.36736.13234.82535.01234.79035.53735.08135.24534.76336.68937.46136.61136.31238.73738.75836.18535.36734.32334.26934.73635.83836.35833.49632.44632.60032.98231.07030.05029.29228.94228.20027.71727.94732.29031.81032.89332.77530.96431.75732.14333.94035.01034.81735.46436.377

40.84139.40839.49143.64045.06145.57246.49245.81745.18144.97745.39945.31046.33644.55443.49544.08943.85944.92845.45142.50241.78242.82945.25146.25547.31947.01745.58345.95647.21247.24248.18549.18848.13248.58149.05549.41550.42150.26350.84849.63348.60348.87948.03048.25448.571

64.6471.4970.8166.7867.4072.4973.4566.6365.5272.8876.1778.3780.3075.5464.8675.3469.6466.9168.6771.7471.6978.0965.4166.0671.7273.6863.1647.3442.9158.3763.5958.0275.0073.5676.2580.2186.4176.0075.5374.8180.7782.1881.8681.3683.27

HHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH

CCCNCCOCONCCOCONCCOCCCNCCOCCCNCNNNCCOCCCNCCOC

310231033104310531063107310831093110311131123113311431153116311731183119312031213122312331243125312631273128312931303131313231333134313531363137313831393140314131423143314431453146

OGNCACOCBCGCDOE1OE2NCACOCBOG1CG2NCACOCBCG1CG2NCACOCBOG1CG2NCACOCBSGNCACOCBCGOD1ND2

SER HGLU HGLU HGLU HGLU HGLU HGLU HGLU HGLU HGLU HTHR HTHR HTHR HTHR HTHR HTHR HTHR HVAL HVAL HVAL HVAL HVAL HVAL HVAL HTHR HTHR HTHR HTHR HTHR HTHR HTHR HCYS HCYS HCYS HCYS HCYS HCYS HASN HASN HASN HASN HASN HASN HASN HASN H

190191191191191191191191191191192192192192192192192193193193193193193193194194194194194194194195195195195195195196196196196196196196196

3.7071.8110.6940.5231.4650.9030.8871.1380.4402.028-0.697-1.035-0.683-1.405-2.536-2.869-2.8950.4260.8360.1490.3282.3602.7183.046-0.644-1.364-1.173-1.145-2.869-3.085-3.622-1.068-0.878-2.215-2.9120.1240.445-2.559-3.807-3.467-2.757-4.535-4.395-4.161-4.541

36.57033.92433.64232.14331.44734.33435.84436.46636.08137.33831.66530.25429.60929.76730.02130.37028.56928.87728.16526.80726.08727.97227.02229.31326.45525.19024.25024.67025.43726.18624.11022.96421.93021.26820.77120.89119.49921.26520.68219.43319.52321.70123.13024.06123.310

47.17447.05246.16245.93445.55844.82044.87943.51842.55243.41746.15045.99844.66343.67946.23047.57745.97844.63643.43243.52944.50943.38442.26543.17042.52542.57541.39040.23742.75243.95242.82541.70240.69940.36541.24841.22240.09839.08138.60637.78736.78537.72838.24737.47239.556

87.4981.1880.6382.1380.4681.6778.6684.1079.1684.6482.9782.0080.5380.7180.0588.1278.2875.9868.2565.3664.6466.8370.8666.1364.2965.1863.5464.2765.8467.5167.6060.7961.1257.7256.1260.8874.4752.6753.5952.3551.7359.8162.0067.8165.11

HHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH

ONCCOCCCOONCCOCOCNCCOCCCNCCOCOCNCCOCSNCCOCCON

314731483149315031513152315331543155315631573158315931603161316231633164316531663167316831693170317131723173317431753176317731783179318031813182318331843185318631873188318931903191

NCACOCBCG1CG2NCACOCBNCACOCBCGND1CD2CE1NE2NCACOCBCGCDNCACOCBNCACOCBOGNCACOCB

VAL HVAL HVAL HVAL HVAL HVAL HVAL HALA HALA HALA HALA HALA HHIS HHIS HHIS HHIS HHIS HHIS HHIS HHIS HHIS HHIS HPRO HPRO HPRO HPRO HPRO HPRO HPROHALA HALA HALA HALA HALA HSER HSER HSER HSER HSER HSER HSER HSER HSER HSER HSER H

197197197197197197197198198198198198199199199199199199199199199199200200200200200200200201201201201201202202202202202202203203203203203

-3.982-3.689-4.930-5.888-2.750-2.412-1.495-4.897-6.021-5.610-4.711-6.910-6.281-6.037-7.384-7.882-5.218-5.003-5.849-4.026-5.403-4.297-7.989-9.277-9.504-10.551-9.236-8.483-7.342-8.523-8.632-9.267-9.869-7.263-9.135-9.708-10.529-11.048-8.602-7.878-10.639-11.383-10.951-11.738-12.888

18.27617.01616.19016.13516.14314.85116.92315.53214.71713.43413.44115.54312.33611.03110.3859.55510.1388.7457.6998.2216.5936.88210.77810.3238.8228.37610.80012.08211.6998.0476.6006.1275.0545.9796.9366.6037.7907.7836.3017.4758.80910.01410.51210.5379.732

38.19937.51237.15937.92538.38137.66638.71836.00235.55134.83233.99334.64335.17434.56134.25035.00235.49634.98235.28134.20334.71334.05333.12032.59332.68933.15231.14631.25532.16732.24432.26933.57833.64132.07934.62035.91236.40037.51636.91937.23435.55235.88737.25338.19035.888

49.5846.5748.5653.4844.4839.0737.4949.5248.5351.0755.9148.5754.8351.2751.9246.1847.9142.9952.9052.6850.6847.6558.5960.7560.2764.2161.9360.3960.1057.2857.9564.2767.2853.2164.0367.5671.6375.1068.0260.7073.8875.6770.0270.1281.76

HHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH

NCCOCCCNCCOCNCCOCCNCCNNCCOCCCNCCOCNCCOCONCCOC

319231933194319531963197319831993200320132023203320432053206320732083209321032113212321332143215321632173218321932203221322232233224322532263227322832293230323132323233323432353236

OGNCACOCBOG1CG2NCACOCBCGCDCENZNCACOCBCG1CG2NCACOCBCG0D1OD2NCACOCBCGCDCENZNCACO

SER HTHR HTHR HTHR HTHR HTHR HTHR HTHR HLYS HLYS HLYS HLYS HLYS HLYS HLYS HLYS HLYS HVAL HVAL HVAL HVAL HVAL HVAL HVAL HASP HASP HASP HASP HASP HASP HASP HASP HLYS HLYS HLYS HLYS HLYS HLYS HLYS HLYS HLYS HLYS HLYS HLYS HLYS H

203204204204204204204204205205205205205205205205205206206206206206206206207207207207207207207207208208208208208208208208208209209209209

-13.367-9.690-9.129-8.638-7.549-7.941-8.377-7.367-9.444-9.041-8.508-9.036-10.240-9.928-11.159-10.866-10.500-7.455-6.865-6.097-5.419-5.879-5.211-6.595-6.211-5.512-4.636-5.119-6.511-7.287-6.681-8.508-3.353-2.431-1.774-1.123-1.348-1.885-2.596-1.633-2.313-1.959-1.396-0.0560.067

9.50210.90811.39512.82513.06910.5239.16911.02113.77915.17115.51215.02716.05517.54118.37419.87520.33416.32316.71018.01518.27015.64816.15114.35418.83520.11920.11819.82121.27821.47721.89921.20720.43920.47121.82922.38719.40818.00417.70617.72817.29622.34823.62423.33622.404

34.57137.35338.60238.46237.95539.03839.19740.34638.89938.82440.20641.20038.47938.48038.14038.21839.59340.27341.55441.45840.46442.08043.34142.36342.50242.58143.83244.92742.65941.36440.35441.35243.67244.80545.02944.14344.64544.65045.95247.13648.39746.23546.63247.30948.111

92.4469.1368.0769.6075.9367.9069.6968.9871.8472.9270.2670.6176.8193.84119.23127.13118.1071.2465.4766.8863.5960.1859.0458.5270.8472.8372.6075.8471.3377.6880.9290.4971.6667.7267.2960.5161.9770.1179.5679.2074.6568.0468.0568.5268.41

HHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH

ONCCOCOCNCCOCCCCNNCCOCCCNCCOCCOONCCOCCCCNNCCO

原子原子原子原子原子原子原子原子原子原子原子原子原子TER原子原子原子原子原子TER原子原子原子原子原子原子原子原子原子原子原子原子原子原子原子原子原子原子原子原子原子原子原子原子原子

323732383239324032413242324332443245324632473248324932503251325232533254325532563257325832593260326132623263326432653266326732683269327032713272327332743275327632773278327932803281

CBCGCDCENZNCACOCBCG1CG2CD1SO5O2O3O4OOOOOOOOOOOOOOOOOOOOOOOOO

LYS HLYS HLYS HLYS HLYS HILE HILE HILE HILE HILE HILE HILE HILE HILE HSO4 ZSO4 ZSO4 ZSO4 ZSO4 ZSO4 ZHOH WHOH WHOH WHOH WHOH WHOH WHOH WHOH WHOH WHOH WHOH WHOH WHOH WHOH WHOH WHOH WHOH WHOH WHOH WHOH WHOH WHOH WHOH WHOH WHOH W

20920920920920921021021021021021021021021011111112345678910111213141516171819202122232425

-2.364-1.838-2.792-2.194-3.0310.9482.3232.6542.9053.2892.7634.6542.724-12.465-11.496-13.354-11.721-13.2846.64228.2294.085-2.722-0.482-9.832-1.203-10.065-4.782-3.602-11.74812.0283.37917.930-0.999-7.18811.612-21.984-13.11311.8995.06810.2498.24227.126-2.011

24.32625.58626.02427.11527.38224.13523.90724.76025.96524.18923.60623.51922.0778.2797.5329.0168.9607.17326.25527.68820.72125.52915.33515.97625.88813.54415.15222.70512.73116.121-3.32521.06421.44420.6916.0229.843-7.72630.8354.55011.29227.27625.65421.099

47.59448.25749.34850.22051.43246.97547.37848.59348.53846.20444.88346.46744.880-5.420-4.640-4.584-6.420-6.13611.50414.33515.2405.31920.340-2.164-0.42833.937-5.6512.193-2.74418.7010.68555.6101.05015.90014.8355.12918.94917.1677.25438.20513.28113.31711.221

1.001.001.001.001.001.001.001.001.001.001.001.001.001.001.001.001.001.001.001.001.001.001.001.001.001.001.001.001.001.001.001.001.001.001.001.001.001.001.001.001.001.001.00

69.9066.7678.3594.1096.3869.4269.3173.8572.2363.4255.8553.5942.80139.70128.34133.20143.54137.6944.2247.6546.9843.8156.3656.0650.4059.0558.1848.1346.3241.7144.5832.5939.3758.6263.8040.9255.8551.4066.6865.9740.5336.2836.94

HHHHHHHHHHHHHZZZZZWWWWWWWWWWWWWWWWWWWWWWWWW

CCCCNNCCOCCCCSOOOOOOOOOOOOOOOOOOOOOOOOOOOOO

原子原子原子原子原子原子原子原子原子原子原子原子原子原子原子原子原子原子原子原子原子原子原子原子原子原子原子原子原子原子原子原子原子原子原子原子原子原子原子TER

3282328332843285328632873288328932903291329232933294329532963297329832993300330133023303330433053306330733083309331033113312331333143315331633173318331933203321

OOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOO

HOH WHOH WHOH WHOH WHOH WHOH WHOH WHOH WHOH WHOH WHOH WHOH WHOH WHOH WHOH WHOH WHOH WHOH WHOH WHOH WHOH WHOH WHOH WHOH WHOH WHOH WHOH WHOH WHOH WHOH WHOH WHOH WHOH WHOH WHOH WHOH WHOH WHOH WHOH WHOH W

26272829303132333435363738394041424344454647484950515253545556575859606162636464

4.1523.465-3.7398.75811.6349.16921.3651.667-0.777-1.9796.5808.78216.06129.64520.575-22.962-21.174-18.93410.166-16.05016.0882.89724.05723.165-11.702-12.21912.3914.767-3.09912.78114.92316.11521.32423.7262.0502.4578.951-6.14110.484

14.4408.41226.15815.4473.61811.5937.67826.7052.9206.4142.3783.2658.4504.1894.76511.03911.68722.0141.1393.11323.61030.1381.22421.91614.692-0.92212.24511.26621.16410.76628.54816.4313.6494.64632.04033.745-2.54527.59922.284

20.40820.717-0.96418.5407.59035.5338.159-2.342-5.893-4.6907.0035.25610.73352.48261.33419.09421.3685.9129.69811.26339.6972.02745.6867.47923.0741.07637.89729.44948.32929.4253.207-9.57164.10063.3783.6735.919-6.7739.56028.826

1.001.001.001.001.001.001.001.001.001.001.001.001.001.001.001.001.001.001.001.001.001.001.001.001.001.001.001.001.001.001.001.001.001.001.001.001.001.001.00

44.3836.2759.4958.2664.9053.9156.3034.3654.0486.5956.1035.2659.2554.6768.6273.8872.7760.2247.4037.9646.5161.2448.9666.8650.0243.8249.9443.9558.5753.4158.1869.8872.2757.0451.7856.7154.1551.6150.78

WWWWWWWWWWWWWWWWWWWWWWWWWWWWWWWWWWWWWWW

OOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOO

^a根据表6及7中所示的Chothia编号系统分别编号轻链(L)和重链(H)的氨基酸残基。

^b各栏根据Protein Data Bank Format，2.2版标记柱。

表11.人IL-13/mAb13.2 Fab的结构坐标^a，b

	#	名称	残基链	残基#	X	Y	Z	occ	B	SegID	Ele
	#	名称	残基链	残基#	X	Y	Z	occ	B	SegID	Ele	原子原子原子原子原子原子原子原子原子原子原子原子原子原子原子原子原子原子原子原子原子原子原子原子原子原子原子原子原子原子原子原子原子原子原子原子原子原子原子原子原子	1234567891011121314151617181920212223242526272829303132333435363738394041	NCACOCBCGOD1OD2NCACOCBCG1CG2CD1NCACOCBCG1CG2NCACOCBCGCD1CD2NCACOCBOG1CG2NCAC	ASP LASP LASP LASP LASP LASP LASP LASP LILE LILE LILE LILE LILE LILE LILE LILE LVAL LVAL LVAL LVAL LVAL LVAL LVAL LLEU LLEU LLEU LLEU LLEU LLEU LLEU LLEU LTHR LTHR LTHR LTHR LTHR LTHR LTHR LGLN LGLN LGLN L	11111111222222223333333444444445555555666	19.93519.85020.68220.89518.40117.47817.95316.27321.22422.04521.09120.17322.96523.82223.83724.90321.34520.48021.21122.37720.13619.35119.33920.50821.16120.54619.32720.91521.45621.32122.89221.39720.89621.37522.58221.39420.96920.80920.42920.78620.774	-6.154-5.026-3.882-3.771-4.586-5.746-6.910-5.483-3.062-1.948-0.844-0.469-1.444-2.608-0.288-2.205-0.2880.7482.0472.1360.4981.686-0.8573.0714.3745.3045.4324.9364.0274.7563.6345.9486.8658.2748.5226.4335.0787.3449.17410.55111.432	103.296102.305102.873104.096102.115101.733101.564101.616101.987102.451102.909102.186101.317100.829101.80099.809104.091104.626104.535104.919106.139106.702106.283104.059103.883104.877104.897102.460101.32599.972101.547105.669106.687106.385106.333108.085108.303109.172106.204105.891107.115	1.001.001.001.001.001.001.001.001.001.001.001.001.001.001.001.001.001.001.001.001.001.001.001.001.001.001.001.001.001.001.001.001.001.001.001.001.001.001.001.001.00	32.5131.6633.1735.1332.5938.5632.4840.4228.0925.5524.7923.2324.0323.1621.5625.0119.6323.3620.6517.6025.7218.8124.1714.4218.7018.2517.1117.3718.4821.8110.4017.4116.6315.6018.7020.6020.7710.8714.4819.2720.35	LLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLL	NCCOCCOONCCOCCCCNCCOCCCNCCOCCCCNCCOCOCNCC

OCBCGCDOE1NE2NCACOCBOGNCACOCBCGCDNCACOCBNCACOCBOGNCACOCBCGCD1CD2NCACOCBNCA

666666777777888888899999101010101010111111111111111112121212121313

20.02319.84820.02619.18518.43819.30421.62921.65922.10522.91922.62623.93521.47620.38819.10819.12920.35220.65721.87117.99216.72816.28015.59715.66416.64516.22117.39418.03514.97314.36617.63418.73618.23617.60119.91521.03421.67922.08518.52318.11719.39820.17917.15719.55920.690

11.19111.09610.32310.95610.29712.27812.43713.37514.73314.83112.92512.94315.79915.76315.44815.32217.21418.01217.18215.35015.08716.34816.30114.66817.50118.77919.75719.66919.28820.37020.65221.64222.96922.99621.17522.16522.49121.57324.07925.37326.24726.27926.06226.90927.848

108.046104.796103.428102.327101.640102.179107.115108.226107.717106.800109.313108.812108.238109.237108.500107.288109.770108.547107.933109.217108.575107.883106.847109.609108.463107.890108.162109.245108.657107.960107.203107.298106.760105.724106.395106.165107.531105.281107.460106.956106.827107.755107.931105.698105.538

1.001.001.001.001.001.001.001.001.001.001.001.001.001.001.001.001.001.0011001.001.001.001.001.001.001.001.001.001.001.001.001.001.001.001.001.001.001.001.001.001.001.001.001.001.00

21.3815.2118.4511.8318.9417.0922.1523.6022.7320.8321.4536.0621.9217.2318.6018.3016.3615.9616.2221.6920.9323.8723.9716.1523.9723.5520.7820.2819.4536.0416.8617.3617.4120.5921.7724.5136.8937.8516.7617.1716.2414.6412.6413.8713.69

LLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLL

OCCCONNCCOCONCCOCCCNCCOCNCCOCONCCOCCCCNCCOCNC

20.16719.05521.81822.28021.35720.92320.46620.79621.70921.20320.99920.07920.33021.82422.35419.46217.92617.18417.74322.47323.84924.83125.99524.40225.30925.51924.87324.77624.88724.58423.62225.40126.40926.66325.83325.74628.18228.48329.80030.93831.43630.89732.48825.26224.505

29.10629.11727.28625.95827.09630.20231.44031.36530.63532.68232.72732.13732.17332.52233.40933.25832.95834.15931.66531.80532.08931.32331.33530.68329.91428.50228.10829.77531.11130.90230.18731.47827.76326.38925.43725.61926.06624.56624.16624.65425.88526.77726.22524.39623.379

104.907104.336104.656105.301103.157105.000104.326102.849102.423104.941106.352102.048100.620100.384101.02599.92799.76499.09098.90599.48399.14499.96499.602101.063101.882101.325100.371103.318104.106105.540105.905106.386101.953101.515102.374103.595101.682101.572102.211101.453101.533102.353100.788101.752102.489

17.2521.7215.0810.629.1815.7114.9114.4913.9311.6918.4813.8916.7917.3821.7414.6934.8644.9132.5616.1412.8214.6018.4410.3412.1513.5314.7717.4010.1817.9024.844.7413.1915.6315.3419.4015.0225.1839.5664.4879.3786.8382.5917.1112.89

LLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLL

COCCCNCCOCONCCOCCCCNCCONCCOCCCONNCCOCCCNCNNNC

COCBNCACOCBOG1CG2NCACOCBCG1CG2CD1NCACOCBOGNCACOCBSGNCACOCBCGCDCENZNCACOCBN

25.19825.48323.05425.47626.09625.22724.81327.53328.29128.20224.89624.06624.76025.49522.64822.64821.98521.21924.55925.28624.46723.26926.24425.51625.10724.38325.37026.49724.04723.31024.96125.87625.31224.16826.08926.98727.32028.35827.74926.12225.59526.02127.13026.14125.176

22.03121.71323.29421.26519.96018.93419.12619.98520.90118.60817.87716.84115.50415.25116.80916.40118.17316.54514.65113.39112.14812.12313.29013.12611.0999.8338.7498.7069.6418.0457.8696.8355.4825.2166.9605.8486.0377.1588.5354.6133.2902.2142.2932.8851.214

102.204101.026101.953103.249103.054103.752104.923103.630102.832103.594103.035103.610103.500102.542103.010101.575103.154100.967104.492104.429104.321104.622105.598106.775103.822103.656104.099103.609102.175101.699105.013105.490105.148105.416107.018107.576109.086109.343109.135104.564104.192105.224105.753102.822105.434

16.5422.7914.8514.1715.5615.6520.8917.9023.2720.0914.4618.3417.5718.2619.0929.5623.7337.8815.9420.9818.5120.3717.2638.0415.1519.9319.0924.0618.3319.0119.8121.4419.4517.2920.1438.3555.6965.7873.9716.5820.9520.0621.6616.4420.89

LLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLL

COCNCCOCOCNCCOCCCCNCCOCONCCOCSNCCOCCCCNNCCOCN

25.50226.61427.25824.23423.57726.84827.88928.48427.83127.29326.25125.81624.83126.51529.69830.35529.56228.96731.77932.40829.57028.82929.84029.46527.76626.67528.44131.12732.17832.33932.21933.53433.66234.76132.67632.61732.79734.09034.14131.69331.88431.80032.14935.16136.460

0.134-0.805-1.521-0.680-1.189-0.797-1.606-0.7230.237-2.881-3.624-4.858-5.516-5.132-1.029-0.237-0.293-1.329-0.778-0.0780.7980.7880.9371.2071.9401.7403.3260.7080.849-0.453-1.5591.1532.5922.9753.331-0.316-1.499-1.203-0.339-1.594-2.785-3.934-2.530-1.861-1.652

106.403105.917106.720106.758105.615104.598103.971102.886102.428103.288104.048103.275103.672102.264102.455101.412100.12899.782101.121100.03799.38398.10396.98195.83798.01099.07298.17297.27996.26895.49796.07196.90897.32697.76497.20894.20693.34492.62391.73592.28391.38491.85290.07193.05192.445

24.5324.4825.9720.8524.4725.2322.2422.0425.8316.5717.0625.6318.3323.8523.9220.0421.0723.9818.9528.1318.2217.7919.5922.0117.5112.9816.6317.3318.2319.5326.3912.1222.3129.8918.1320.9022.4423.2125.3120.7224.8424.3723.2623.8821.04

LLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLL

CCOCONCCOCCCOONCCOCONCCOCCCNCCOCCOONCCOCCONNC

COCBCGCD1CD2CE1CE2CZOHNCACONCACOCBCGCDCENZNCACOCBOGNCACOCBCGCD1CD2NCACOCBCGSDCE

36.82337.12336.56736.52037.58035.42737.54235.37536.44536.42936.77437.17836.10136.35534.92533.83332.76732.40733.19533.94935.09734.64135.86932.26331.26629.87629.55931.52832.77229.06827.73726.66125.75927.41028.52828.09828.84126.80525.85825.42426.26826.52225.43824.45725.482

-0.2300.166-2.494-3.965-4.556-4.754-5.890-6.104-6.657-7.9740.5601.9512.9334.1222.4373.3283.3062.2302.8073.1562.1950.783-0.0544.4884.4934.5525.5085.7185.5433.5333.4444.1093.4441.9461.268-0.1132.1155.4226.2437.4008.0606.8577.5756.3175.831

92.17391.03891.17691.53492.21591.21192.55691.55392.22992.59193.23693.12692.67692.63592.30691.84592.94393.38290.55489.27788.99788.73288.51893.36294.45093.81793.13595.36996.01894.04793.41494.27194.74393.12292.24091.81290.95694.44695.22894.30693.66496.48297.43798.20399.589

18.9521.3519.6426.6717.8330.0428.9938.1032.1434.6120.1421.2025.3629.5122.8323.0422.3617.3324.6629.6426.5821.8825.7116.4114.4712.8717.7313.319.7414.8415.2115.3315.9014.1916.6819.0216.7515.1415.5114.1214.6916.8911.5825.2811.25

LLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLL

COCCCCCCCONCCONCCOCCCCNNCCOCONCCOCCCCNCCOCCSC

24.11423.56622.67222.16322.70923.39224.56823.06124.93224.03722.47821.65820.55720.79322.52523.52924.84223.34625.49124.58822.24224.75622.39623.64319.36218.21217.61417.68117.08117.54518.20717.39818.73917.90718.57819.18016.98116.25414.78314.44416.64915.84516.20615.91616.857

7.6218.6499.5299.0627.9886.8166.9505.5015.7704.87410.77011.73112.32112.66512.91412.53212.16712.61012.02712.30212.92812.30012.93312.62212.47013.00514.17814.23311.94210.6679.66010.5268.5349.4148.4367.38515.07216.18015.95615.60617.51518.74919.92619.88520.947

94.23993.36994.23595.28392.27891.61990.89691.56290.42990.81593.80694.60393.73092.57795.12396.14895.94197.56097.15898.16498.38199.55199.730100.32094.30693.59394.36095.57993.46492.77193.48891.39192.82090.72991.44590.76893.62094.25293.94192.79493.60094.02893.10391.88793.659

11.2410.8113.287.469.2119.5118.8919.958.5618.3511.9714.2214.5713.6812.3418.1113.8015.537.3210.4122.7716.3910.7411.4113.7313.3212.8711.7413.0411.479.5012.4512.9610.4212.5613.3810.2511.7013.1617.2610.5910.7215.2616.0213.48

LLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLL

NCCOCCNCCNNCCOCCCCNCCCCCNCCOCCCCCCCONCCOCCCON

NCACOCBCGCDOE1NE2NCACOCBCGCDCENZNCACOCBCGCDNCACONCACOCBCGCDOE1NE2NCACOCBOGN

13.91612.47011.80411.82811.83510.3549.74810.1228.83411.25410.5059.0478.49210.62412.02412.10913.52513.7238.3846.9846.1296.2266.6377.9268.9545.3634.5065.2024.5766.5107.2377.8567.9218.3867.9509.1278.96510.3038.3408.98510.49010.9868.8319.85111.186

16.21216.14017.34317.50914.90114.80513.49813.01112.93518.17019.35518.96518.00420.46720.99421.96222.46023.04019.70819.51119.31520.10420.81921.16820.88818.23017.94617.57217.50317.32516.95515.58415.04717.95919.35720.23421.42119.63915.02613.74413.98815.10413.04113.44312.953

94.92194.68095.32696.56395.31394.96895.49196.54594.72694.45794.87995.08394.49393.81793.60792.44092.19790.80595.96996.31095.04594.12297.03697.72996.65395.00293.86292.56891.52392.62691.42491.60792.69791.12490.72990.24290.00290.09490.50690.58790.93090.80289.21388.33491.401

17.7720.7721.4022.6319.4213.8619.6814.2619.9924.7326.9531.2827.6725.3728.2425.8941.5539.6237.7140.2437.3935.5344.2142.8639.1236.7436.8535.8835.0935.2728.2425.8625.2529.7234.6345.6050.4747.2722.4423.1721.0219.0024.3131.7119.03

LLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLL

NCCOCCCONNCCOCCCCNNCCOCCCNCCONCCOCCCONNCCOCON

CACOCBCGCDNCACOCBNCACOCBCGCD1CD2NCACOCBCGCD1CD2NCACOCBCG1CG2CD1NCACOCBCGCD1CD2CE1CE2

PRO LPRO LPRO LPRO LPRO LPRO LALA LALA LALA LALA LALA LLEU LLEU LLEU LLEU LLEU LLEU LLEU LLEU LLEU LLEU LLEU LLEU LLEU LLEU LLEU LLEU LILE LILE LILE LILE LILE LILE LILE LILE LTYR LTYR LTYR LTYR LTYR LTYR LTYR LTYR LTYR LTYR L

444444444444454545454546464646464646464747474747474747484848484848484849494949494949494949

12.61913.40312.97112.96311.56810.63014.57615.40016.83317.28715.30017.54518.94819.84119.82519.41620.87521.07421.26920.63021.57823.03823.77421.55620.21520.36219.91123.42224.80024.82124.06625.44425.46526.84226.42225.65125.69827.11828.11425.22326.07927.10025.84027.87626.620

13.05613.34412.99711.67511.16311.64513.94214.21713.92114.31815.70213.28512.90314.15414.94411.89411.40810.59110.53314.32315.43915.01415.64915.99716.58716.81217.87913.95213.46811.95311.26313.82615.35113.13616.16511.4249.9779.48410.1779.4499.8999.10511.1319.53111.584

91.73890.45489.33992.30492.90191.78690.60389.42889.84690.92789.00088.94889.21289.20688.24788.10788.32089.66087.11190.27790.38490.15089.39391.78992.28993.81091.52290.85690.88390.75491.44392.28192.49592.43191.51989.86089.79090.10789.86988.41987.24686.73386.64685.63285.542

19.5719.1717.2720.3314.2617.9814.9415.7615.7114.3417.7915.1411.8512.8512.839.188.528.067.6111.8111.3711.2213.3211.4011.7511.874.8012.5310.5214.3316.1311.939.2811.5814.2912.8014.4513.7514.876.5014.449.6320.1718.3322.28

LLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLL

CCOCCCNCCOCNCCOCCCCNCCOCCCCNCCOCCCCNCCOCCCCCC

CZOHNCACOCBCGCDNECZNH1NH2NCACOCBNCACOCBOGNCACOCBCGOD1ND2NCACOCBCGCD1CD2NCACOCB

TYR LTYR LARG LARG LARG LARG LARG LARG LARG LARG LARG LARG LARG LALA LALA LALA LALA LALA LSER LSER LSER LSER LSER LSER LASN LASN LASN LASN LASN LASN LASN LASN LLEU LLEU LLEU LLEU LLEU LLEU LLEU LLEU LGLU LGLU LGLU LGLU LGLU L

494950505050505050505050505151515151525252525252535353535353535354545454545454545555555555

27.62428.37227.17628.46129.31130.48029.22830.08430.93330.07330.54331.85229.72728.62129.12529.53129.25530.28830.11930.65230.43730.88432.17932.74729.74729.57528.30127.22829.46130.75631.78730.73028.44327.29626.43826.92827.86626.79326.01327.47325.15224.27124.09923.95222.935

10.77811.2578.2797.6178.5308.7957.2935.9985.8205.9426.2276.4046.3549.0319.88611.30912.1909.17711.55512.88713.42714.54212.85111.79712.67713.14313.95313.46811.95411.17211.7059.94815.14316.07515.65915.57217.49818.59018.66720.00115.43715.05616.20617.35614.633

85.04983.98790.64890.96291.87191.58389.67389.78488.46087.25286.03785.85885.00392.90193.97593.68094.48194.72792.50992.21490.81590.50492.47691.67289.96288.56188.43988.81387.63087.59487.17888.07987.88087.72586.53985.40087.49987.33688.68886.93586.79285.71584.68485.03586.323

20.5719.1114.1116.5216.0414.9512.6215.1011.2623.5220.3726.1818.2414.0114.1916.6315.016.7714.3512.9010.839.895.6419.1810.806.0213.2915.209.0415.9724.4323.8912.2711.1913.2617.409.359.3511.2410.0613.1913.5016.4016.6617.40

LLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLL

CONCCOCCCNCNNNCCOCNCCOCONCCOCCONNCCOCCCCNCCOC

CGCDOE1OE2NCACOCBOGNCACONCACOCBCG1CG2CD1NCACOCBCGCDNCACOCBNCACOCBCGCDNECZNH1NH2

GLU LGLU LGLU LGLU LSER LSER LSER LSER LSER LSER LGLY LGLY LGLY LGLY LILE LILE LILE LILE LILE LILE LILE LILE LPRO LPRO LPRO LPRO LPRO LPRO LPRO LALA LALA LALA LALA LALA LARG LARG LARG LARG LARG LARG LARG LARG LARG LARG LARG L

555555555656565656565757575758585858585858585959595959595960606060606161616161616161616161

21.89122.17423.18921.36624.14123.95922.66021.61023.89323.69622.73521.54021.38320.60422.13022.07723.21024.35322.32121.24822.29319.77122.93324.01125.12724.88823.29622.11921.70226.34227.48227.44328.37028.82826.38226.25926.07626.22225.01524.95823.75922.42821.59421.95220.455

14.25712.93012.22712.58315.87316.91017.69217.08916.26017.28019.01719.83220.33621.23919.75820.19921.22520.97218.98517.92519.43318.43622.35123.32422.85722.11924.56724.01322.76623.35222.93623.43623.16423.38924.14124.48523.17123.16625.35526.56727.52827.03626.43826.27925.955

85.23884.53884.87983.64283.39082.37082.62882.90780.97279.99082.56482.79484.21984.47085.15486.55986.77586.37687.47987.20588.95787.37387.47187.65088.58689.55188.18188.93288.16688.33589.14190.58891.34988.43990.97992.40893.22494.44892.61091.63491.98291.55892.40593.67091.970

18.7121.3729.0914.3518.4521.0220.4523.0023.3035.0516.0515.7917.4820.7615.6313.5414.5715.4116.1410.8414.427.9616.5715.0217.6820.8113.0914.5516.3715.0315.8016.3714.1019.0313.8612.6613.3311.6210.5021.5634.9220.5119.5020.7618.94

LLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLL

CCOONCCOCONCCONCCOCCCCNCCOCCCNCCOCNCCOCCCNCNN

NCACOCBCGCD1CD2CE1CE2CZNCACOCBOGNCACONCACOCBOGNCACONCACOCBOGNCACOCBCGCDNE

PHE LPHE LPHE LPHE LPHE LPHE LPHE LPHE LPHE LPHE LPHE LSER LSER LSER LSER LSER LSER LGLY LGLY LGLY LGLY LSER LSER LSER LSER LSER LSER LGLY LGLY LGLY LGLY LSER LSER LSER LSER LSER LSER LARG LARG LARG LARG LARG LARG LARG LARG L

626262626262626262626263636363636364646464656565656565666666666767676767676868686868686868

25.68225.54526.81627.28224.37823.01922.35922.47821.17521.24820.63127.35428.54228.45027.74029.84129.86429.17629.11230.47431.36330.65731.92731.70930.59732.91432.30432.79532.71133.14533.44533.21533.59133.24132.99035.10335.79233.19332.87531.49430.48634.00335.38936.41637.790

22.08620.77119.96819.87519.98820.61220.34421.53320.99422.22021.93219.37518.51817.38417.51219.32619.82116.29015.21414.68914.81314.09713.48612.31012.05614.49114.96711.58210.4629.1689.1448.0996.7845.8176.2206.6946.8174.5503.4633.5453.1753.3523.0702.8963.179

92.54693.17492.95091.81892.50792.79394.00591.92994.34392.27893.48094.00093.80194.81795.80394.05195.38394.59295.55995.84694.99597.03197.36198.32698.75298.01199.19398.63099.55198.88697.69699.67399.170100.287101.44498.886100.13699.906100.793101.440100.813101.843101.227102.374101.986

11.0613.4614.5814.6410.2511.0414.5711.679.155.0215.5113.2816.6916.9313.9920.8015.2215.1512.8517.0520.0414.7417.9015.6410.2917.3731.0817.4912.0817.5720.8117.2217.3318.0016.6014.4315.1318.0221.9023.1022.8522.7626.6048.1367.04

LLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLL

NCCOCCCCCCCNCCOCONCCONCCOCONCCONCCOCONCCOCCCN

CZNH1NH2NCACOCBOG1CG2NCACOCBCGOD1OD2NCACOCBCGCD1CD2CE1CE2CZNCACOCBOG1CG2NCACOCBCGCD1CD2N

ARG LARG LARG LTHR LTHR LTHR LTHR LTHR LTHR LTHR LASP LASP LASP LASP LASP LASP LASP LASP LPHE LPHE LPHE LPHE LPHE LPHE LPHE LPHE LPHE LPHE LPHE LTHR LTHR LTHR LTHR LTHR LTHR LTHR LLEU LLEU LLEU LLEU LLEU LLEU LLEU LLEU LTHR L

686868696969696969697070707070707070717171717171717171717172727272727272737373737373737374

38.46637.90239.73731.43130.14429.69828.59230.15831.16630.52330.51730.15830.23831.29031.11831.03330.02831.95429.12429.04128.41127.69128.13828.70928.52329.57929.22330.26830.08428.62427.99827.57528.19628.96430.05829.54226.49326.03026.21725.78324.51323.86224.36422.33326.779

4.2895.2574.4174.0234.1145.5455.7263.3063.8561.8206.5527.9268.8639.0318.4357.5867.6936.8009.52610.42611.73911.7979.7668.4637.2848.4626.0627.3016.09212.76514.03514.67514.43515.02015.25014.43615.45716.23617.67717.97615.99616.93316.62216.77818.549

102.301103.019101.918102.691103.374103.712104.182104.710105.554104.424103.434103.803102.615102.016104.889106.173106.878106.428102.329101.185101.605102.608100.10999.614100.32598.52599.95198.15398.878100.801101.08199.75198.717101.770100.913103.03099.80798.66399.201100.32298.41597.41295.97197.42598.366

77.7274.0883.9224.7727.1326.5128.1426.9127.9625.3120.5622.6320.6826.5626.7433.1745.6248.3517.2918.0716.3114.0416.2715.3911.667.2512.247.988.5017.2017.6219.3120.8815.5523.8215.8219.7216.5514.6618.4612.0415.167.1210.1215.06

LLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLL

CNNNCCOCOCNCCOCCOONCCOCCCCCCCNCCOCOCNCCOCCCCN

CACOCBOG1CG2NCACOCBCG1CG2CD1NCACOCBCGOD1ND2NCACOCBCGCDNCACOCBCG1CG2NCACOCBCGCDOE1OE2

THR LTHR LTHR LTHR LTHR LTHR LILE LILE LILE LILE LILE LILE LILE LILE LASN LASN LASN LASN LASN LASN LASN LASN LPRO LPRO LPRO LPRO LPRO LPRO LPRO LVAL LVAL LVAL LVAL LVAL LVAL LVAL LGLU LGLU LGLU LGLU LGLU LGLU LGLU LGLU LGLU L

747474747474757575757575757576767676767676767777777777777778787878787878797979797979797979

27.00126.27126.29728.49729.13628.71925.52024.84225.51525.48123.33122.75622.64321.23926.08526.80327.02227.64028.15928.92028.30230.24426.46725.63224.20523.72125.65125.60126.62123.51622.08621.23721.52821.65920.10822.22520.22919.30317.89017.67919.34120.70320.77121.81119.829

19.93120.79220.51320.27419.50821.79321.78422.71724.05224.50122.80921.38723.70321.34824.70325.94126.79726.37825.53526.73827.68226.69028.00528.64428.12627.85230.13530.05828.85428.05127.65028.80930.00627.34227.33825.96228.48229.45229.10828.01129.35429.70129.89230.36229.549

98.74597.74496.53298.75699.77799.06898.23397.35297.68798.85597.65697.59796.64197.96396.69197.02595.78994.82997.65598.20598.68198.17595.75796.79396.66595.56796.41494.80794.56097.79497.77397.19897.45899.24099.34499.69196.38595.77796.28096.72894.25793.73192.19891.74991.476

14.5016.1520.5514.0110.918.5116.3016.6720.5221.7320.9814.607.6310.7218.7518.8319.1420.6620.0720.6120.9625.6422.2322.2422.2923.3720.0318.0119.6019.3015.8615.0218.6210.7615.658.7015.6615.4819.0018.7516.5217.3331.9736.0719.91

LLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLL

CCOCOCNCCOCCCCNCCOCCONNCCOCCCNCCOCCCNCCOCCCOO

NCACOCBNCACOCBCGOD1OD2NCACOCBCGOD1OD2NCACOCBCG1CG2NCACOCBNCACOCBOG1CG2NCACOCB

ALA LALA LALA LALA LALA LASP LASP LASP LASP LASP LASP LASP LASP LASP LASP LASP LASP LASP LASP LASP LASP LVAL LVAL LVAL LVAL LVAL LVAL LVAL LALA LALA LALA LALA LALA LTHR LTHR LTHR LTHR LTHR LTHR LTHR LTYR LTYR LTYR LTYR LTYR L

808080808081818181818181818282828282828282838383838383838484848484858585858585858686868686

16.94615.59414.94114.20214.65515.18114.49215.08314.61414.46713.57512.39814.05416.05716.64015.83916.14418.08819.01618.68520.08114.81014.00813.42712.82012.91413.60412.22713.65113.27213.73214.33614.07113.41613.96015.00514.72712.84511.92013.47016.18317.26817.44717.45818.564

30.04129.80428.59627.90231.03428.37427.25425.90324.88927.44426.43026.28425.76425.87124.58723.92122.77924.76125.23625.11925.77724.60923.95722.66222.65024.90525.94225.58221.57620.26919.24019.57620.05617.95916.88816.21015.96715.85516.52114.65715.91615.30913.87913.63716.109

96.17996.72896.12596.79796.43294.83994.18494.53393.99192.65891.93892.31990.98295.45395.88797.03897.47096.32895.16193.92595.53197.55398.61798.02096.94899.174100.04698.13098.73898.21899.214100.25396.90098.93099.73998.84397.667100.140101.021100.91899.41198.66799.156100.33098.896

17.4215.6917.3720.2817.8119.1120.1318.9022.6120.2134.8748.8150.2416.9815.0115.7219.3013.5819.8115.9922.5415.1018.0517.3617.4815.9423.4925.1815.6314.8415.5515.8414.4015.7115.4515.1215.9317.0322.018.7214.0413.1316.6918.9411.97

LLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLL

NCCOCNCCOCCOONCCOCCOONCCOCCCNCCOCNCCOCOCNCCOC

CGCD1CD2CE1CE2CZOHNCACOCBCGCD1CD2CE1CE2CZOHNCACOCBSGNCACOCBCGCDOE1NE2NCACOCBCGCDOE1NE2NCA

TYR LTYR LTYR LTYR LTYR LTYR LTYR LTYR LTYR LTYR LTYR LTYR LTYR LTYR LTYR LTYR LTYR LTYR LTYR LCYS LCYS LCYS LCYS LCYS LCYS LGLN LGLN LGLN LGLN LGLN L6LN LGLN LGLN LGLN LGLN LGLN LGLN LGLN LGLN LGLN LGLN LGLN LGLN LSER LSER L

868686868686868787878787878787878787878888888888888989898989898989899090909090909090909191

18.44317.81118.87217.59018.67818.04317.88817.55917.72119.00219.32616.61815.23514.46114.68413.15613.35812.62111.31319.67320.81320.23519.13621.96221.46420.94420.46821.69222.59119.56118.98819.71319.76620.25021.74422.91322.51721.39923.52722.59822.59823.54521.51823.47323.290

17.49118.51617.73419.77218.95519.96821.17712.93611.53310.93511.19510.68411.01811.98510.31812.22810.57211.51011.79910.0999.3677.9617.5929.2418.5757.2205.9175.1015.6526.1384.8584.5275.3483.3103.8252.9941.9391.4362.2851.298-0.129-0.566-0.8581.6410.693

98.30598.98197.00698.36496.38997.05696.44798.21498.58798.05596.89497.96398.45797.82499.51898.24699.94199.30699.71698.85098.27297.90298.35799.263100.91097.04196.58896.15695.50795.39294.74893.43392.49093.36496.54296.19695.19495.20997.41598.11097.52196.86497.80094.32293.251

11.607.5312.0011.0911.3417.2315.7916.9213.5812.8618.146.4718.9811.5614.1315.507.0917.6118.179.8414.4015.1018.4212.7216.0411.359.9613.5614.179.478.4312.8113.057.9912.7311.3612.248.649.8114.9918.0515.8820.5713.9519.79

LLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLL

CCCCCCONCCOCCCCCCCONCCOCSNCCOCCCONNCCOCCCONNC

COCBOGNCACOCBCGOD1ND2NCACOCBCGCDOE1OE2NCACOCBCGOD1OD2NCACOCBCGCDNCACOCBCGCD1CD2NE1

SER LSER LSER LSER LASN LASN LASN LASN LASN LASN LASN LASN LGLU LGLU LGLU LGLU LGLU LGLU LGLU LGLU LGLU LASP LASP LASP LASP LASP LASP LASP LASP LPRO LPRO LPRO LPRO LPRO LPRO LPRO LTRP LTRP LTRP LTRP LTRP LTRP LTRP LTRP LTRP L

919191919292929292929292939393939393939393949494949494949495959595959595969696969696969696

24.35224.61123.44122.23724.93025.98925.42226.01527.04028.30728.83128.77024.27923.64322.16421.54223.77225.16425.37324.42226.51721.58420.12319.62020.27819.74620.19520.45320.25518.47317.66318.31318.88016.32516.74817.83218.19018.75117.88816.66818.59619.49720.29219.69421.009

-0.403-1.0401.4252.067-0.634-1.659-3.053-4.064-1.288-2.149-2.324-2.700-3.143-4.433-4.332-3.325-4.934-5.095-5.930-6.153-6.309-5.438-5.480-5.956-6.748-6.525-6.159-4.967-7.058-5.447-4.449-3.067-2.731-4.466-4.764-5.859-2.249-0.916-0.227-0.463-0.141-0.624-1.7010.007-1.785

93.32592.29891.88791.58694.51094.62094.89094.46095.67695.54594.45096.65695.56295.78395.54095.80497.26197.61298.88799.63899.03295.12394.98396.36697.00893.96292.57392.33691.71896.83696.11296.21097.24396.86598.30898.10495.16995.28596.33996.36493.99492.92492.95491.65791.775

18.6719.3615.1233.4216.1215.6314.3016.7115.7114.4527.5725.9316.6616.6818.7420.0320.2624.6627.3520.4031.5720.6317.1616.5021.4318.3022.9731.4933.2318.3615.5915.0315.5115.2419.8418.4912.5311.4315.4216.136.2918.2623.0015.2715.73

LLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLL

COCONCCOCCONNCCOCCCOONCCOCCOONCCOCCCNCCOCCCCN

CE2CE3CZ2CZ3CH2NCACOCBOG1CG2NCACOCBCGCD1CD2CE1CE2CZNCACONCACONCACONCACOCBOG1CG2NCAC

TRP LTRP LTRP LTRP LTRP LTHR LTHR LTHR LTHR LTHR LTHR LTHR LPHE LPHE LPHE LPHE LPHE LPHE LPHE LPHE LPHE LPHE LPHE LGLY LGLY LGLY LGLY LGLY LGLY LGLY LGLY LGLY LGLY LGLY LGLY LTHR LTHR LTHR LTHR LTHR LTHR LTHR LLYS LLYS LLYS L

969696969697979797979797989898989898989898989899999999100100100100101101101101102102102102102102102103103103

20.65019.14821.09219.58320.55218.52117.78418.05119.06318.16019.58817.56117.11917.17317.29216.79515.89815.72115.20416.00414.98115.77015.25917.98418.02716.63715.79616.42415.14714.89113.80315.91015.66216.10016.04416.57716.96316.24316.35818.52619.19418.81315.48814.75615.578

-0.7441.137-0.3971.4980.7290.6361.3062.8043.2760.7420.642-0.7283.5154.9665.3864.6765.5725.5224.3906.6484.3886.6445.5036.5117.0557.6107.7358.0228.55310.00410.53310.69512.05313.10812.86814.23915.38316.55616.83115.65414.61817.04217.27918.40519.704

90.96491.05889.68189.78789.11897.15398.21298.22997.70799.57099.61899.74998.85198.957100.417101.31398.43596.95296.33596.17394.96694.80894.217100.661102.027102.318101.424103.565103.982103.583103.828103.040102.574103.567104.775103.050103.902103.300102.080103.915104.653104.578104.130103.615103.729

22.2013.0823.5029.6923.2314.0714.3116.1818.7913.4917.2810.3416.7415.2414.9913.0112.9113.5811.5210.3210.7513.2815.2313.5510.5412.589.9412.368.7015.6017.4915.3418.8117.2918.5015.7013.9612.4611.1213.1918.457.0611.4513.9512.14

LLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLL

CCCCCNCCOCOCNCCOCCCCCCCNCCONCCONCCONCCOCOCNCC

OCBCGCDCENZNCACOCBCGCD1CD2NCACOCBCGCDOE1OE2NCACOCBCG1CG2CD1NCACBCONCACOCBCGCDNECZ

LYS LLYS LLYS LLYS LLYS LLYS LLEU LLEU LLEU LLEU LLEU LLEU LLEU LLEU LGLU LGLU LGLU LGLU LGLU LGLU LGLU LGLU LGLU LILE LILE LILE LILE LILE LILE LILE LILE LLYS LLYS LLYS LLYS LLYS LARG LARG LARG LARG LARG LARG LARG LARG LARG L

103103103103103103104104104104104104104104105105105105105105105105105106106106106106106106106107107107107107108108108108108108108108108

16.09813.41112.75911.18510.5339.00015.68916.47015.47214.49417.31618.15319.24318.75815.73814.88315.77716.99514.05812.82211.99112.55010.77215.16715.89715.59414.42315.45415.65116.16517.08216.62216.39117.50716.34117.31615.20815.11014.59714.54714.15112.73511.67211.42010.862

19.99618.60919.92219.91719.24219.15620.45321.72722.91222.98921.89623.20423.20023.35123.83825.04826.26626.15224.99624.03323.73223.40323.79927.40928.69129.51529.65529.52028.72330.88428.29030.02030.90230.81232.31232.76533.00134.37535.31034.97434.39733.97134.63936.01236.858

104.795104.360103.933103.860105.063104.966102.641102.700102.763101.964101.444101.382102.46599.967103.669103.776103.798104.094105.055104.818106.069107.145105.946103.518103.477104.702105.047102.269100.961102.287100.736105.397106.544107.505105.953105.330106.064105.588106.685107.860104.397104.784103.903104.351103.466

16.9011.0025.3032.6242.6551.7611.4014.0316.1219.8617.0815.2114.4221.8819.7423.0321.6623.8520.7042.6441.2048.8035.5419.4918.7818.9217.7418.4523.3617.3911.4618.8718.2113.4021.7526.6324.6823.0922.4826.6719.0822.2721.2420.0020.00

LLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLL

OCCCCNNCCOCCCCNCCOCCCOONCCOCCCCNCCCONCCOCCCNC

NH1NH2NCACOCBNCACOCBCGOD1OD2NCACOCBNCACOCBNCACOCBCGCDNCAC0CBOG1CG2NCACOCBCG1

ARG LARG LALA LALA LALA LALA LALA LASP LASP LASP LASP LASP LASP LASP LASP LALA LALA LALA LALA LALA LALA LALA LALA LALA LALA LPRO LPRO LPRO LPRO LPRO LPRO LPRO LTHR LTHR LTHR LTHR LTHR LTHR LTHR LVAL LVAL LVAL LVAL LVAL LVAL L

108108109109109109109110110110110110110110110111111111111111112112112112112113113113113113113113114114114114114114114115115115115115115

10.55510.61414.24513.72912.31211.49713.73011.90410.5269.5169.78410.29711.02011.59310.9698.3577.3305.9605.6257.3985.1473.8602.8732.8693.2211.9570.994-0.051-0.4270.3520.4781.853-0.511-1.625-2.839-2.946-1.439-0.309-2.655-3.752-4.897-6.170-6.455-5.104-6.171

36.44138.12036.53937.50337.14236.64138.88337.54537.26837.93439.00537.80537.00335.92137.44637.30537.90137.58736.42137.37838.60838.33337.69837.98139.65336.86736.25837.19338.12935.15235.66436.29836.94737.72536.80835.71437.95538.82738.60437.26336.42336.85038.05336.54335.567

102.250103.825106.266107.229107.681106.918106.570108.886109.294108.346107.830110.698111.751111.458112.915108.118107.280107.893108.163105.886108.115108.766107.817106.647109.324108.343107.426106.895107.573108.274109.662109.688105.679105.138105.388104.786103.644103.460103.050106.255106.654105.944105.906108.159108.620

20.0020.0022.1025.9028.1928.8619.2824.1721.5623.6622.7619.3326.8025.3038.9921.5717.9920.0722.2411.3318.9418.4220.5625.1715.7719.4817.0117.5021.6716.8310.9217.6221.8221.6224.8025.8424.0325.1215.6422.0021.6023.5122.6718.3018.51

LLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLL

NNNCCOCNCCOCCOONCCOCNCCOCNCCOCCCNCCOCOCNCCOCC

CG2NCACOCBOGNCACOCBCG1CG2CD1NCACOCBCGCD1CD2CE1CE2CZNCACOCBCGCDNCACOCBCGCDNCACOCB

VAL LSER LSER LSER LSER LSER LSER LILE LILE LILE LILE LILE LILE LILE LILE LPHE LPHE LPHE LPHE LPHE LPHE LPHE LPHE LPHE LPHE LPHE LPRO LPRO LPRO LPRO LPRO LPRO LPRO LPRO LPRO LPRO LPRO LPRO LPRO LPRO LSER LSER LSER LSER LSER L

115116116116116116116117117117117117117117117118118118118118118118118118118118119119119119119119119120120120120120120120121121121121121

-3.743-6.920-8.177-9.200-8.878-8.003-6.991-10.438-11.452-12.594-12.884-11.980-12.950-12.633-13.317-13.211-14.262-15.490-15.406-13.776-12.558-11.308-12.653-10.145-11.486-10.252-16.671-17.866-18.187-17.649-18.993-18.289-16.957-19.111-19.548-20.169-20.757-20.626-20.336-19.783-20.021-20.559-22.061-22.508-19.906

36.26235.87836.13135.12533.96335.93036.77735.56534.62734.56435.57235.02833.96436.42134.19733.38333.21432.51231.42732.38232.92732.63433.80533.22534.39534.10433.10232.40131.23631.10533.44134.76834.49630.37529.21229.76630.85928.59029.03130.45529.03329.46129.14428.27828.677

108.930105.413104.679105.173105.281103.162102.687105.478105.968104.970104.306107.384107.891107.356109.365104.839103.861104.373104.918102.677102.032102.550100.964102.011100.420100.948104.161104.643103.755102.623104.512104.438103.742104.207103.454102.153102.165104.336105.688105.534101.05599.73999.748100.48298.591

15.6421.1819.6720.7519.1416.4731.4918.4219.1918.2119.4820.8816.1821.5321.5316.8414.9619.7424.0816.3219.4923.1516.2227.6018.9819.7524.0921.8822.9925.3321.5724.5823.4624.9720.3522.3427.5321.4324.1026.5026.1328.8030.8928.9829.25

LLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLL

CNCCOCONCCOCCCCNCCOCCCCCCCNCCOCCCNCCOCCCNCCOC

OGNCACOCBOGNCACOCBCGCDOE1OE2NCACOCBCGCDOE1NE2NCACOCBCGCD1CD2NCACOCBOG1CG2NCACOCB

SER LSER LSER LSER LSER LSER LSER LGLU LGLU LGLU LGLU LGLU LGLU LGLU LGLU LGLU LGLN LGLN LGLN LGLN LGLN LGLN LGLN LGLN LGLN LLEU LLEU LLEU LLEU LLEU LLEU LLEU LLEU LTHR LTHR LTHR LTHR LTHR LTHR LTHR LSER LSER LSER LSER LSER L

121122122122122122122123123123123123123123123123124124124124124124124124124125125125125125125125125126126126126126126126127127127127127

-20.172-22.831-24.266-24.432-25.288-24.935-24.460-23.571-23.659-23.564-24.316-22.554-22.812-22.019-22.009-21.405-22.619-22.495-23.678-24.172-21.142-21.002-19.695-19.129-19.218-24.128-25.255-26.482-27.160-25.574-24.497-24.696-24.556-26.753-27.880-27.736-28.733-28.021-26.987-27.929-26.517-26.319-26.420-26.321-24.949

27.28429.85529.60528.19427.47030.59430.37627.77626.40825.35724.37726.17726.92328.18828.96628.37825.53324.53924.58723.54724.69323.70023.78524.87222.62825.78125.92325.15024.43927.40428.13029.65027.61125.26424.50822.99322.28224.67823.91326.17022.48321.04020.70519.53320.596

98.68698.91698.86298.36098.81197.90396.60097.43696.93698.04298.04995.91394.64394.52495.52293.43498.978100.046101.005101.459100.827101.992102.732102.862103.260101.331102.246101.714102.467102.442103.268103.236104.698100.42499.876100.109100.04198.37697.74597.960100.366100.592102.055102.478100.094

28.4533.3734.5630.8631.2836.9048.8628.1833.3530.7728.3235.4849.3960.6360.8360.1930.7327.4625.1925.4328.3817.6219.1220.5814.1923.5826.9931.0731.0121.8026.328.3620.8433.0735.6538.9245.1637.0749.4427.8138.1034.6834.0739.8334.83

LLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLL

ONCCOCONCCOCCCOONCCOCCCONNCCOCCCCNCCOCOCNCCOC

9879889899909919929939949959969979989991000100110021003100410051006100710081009101010111012101310141015101610171018101910201021102210231024102E102610271028102910301031

OGNCACONCACONCACOCBNCACOCBOGNCACOCBCG1CG2NCACOCBCG1CG2NCACOCBSGNCACOCB

SER LGLY LGLY LGLY LGLY LGLY LGLY LGLY LGLY LALA LALA LALA LALA LALA LSER LSER LSER LSER LSER LSER LVAL LVAL LVAL LVAL LVAL LVAL LVAL LVAL LVAL LVAL LVAL LVAL LVAL LVAL LCYS LCYS LCYS LCYS LCYS LCYS LPHE LPHE LPHE LPHE LPHE L

127128128128128129129129129130130130130130131131131131131131132132132132132132132133133133133133133133134134134134134134135135135135135

-24.807-26.596-26.717-25.440-25.456-24.353-23.092-22.632-23.196-21.609-21.095-19.650-19.376-21.909-18.732-17.320-16.890-17.229-16.504-16.912-16.156-15.639-14.114-13.500-15.862-15.461-17.369-13.531-12.110-11.267-11.670-11.935-10.401-12.729-10.052-9.164-7.833-7.335-8.948-7.928-7.314-5.972-5.009-5.343-5.953

20.84521.73021.46921.69721.61222.02022.20723.63524.52423.85925.20525.16425.01625.94025.32925.33626.77827.50424.48923.13927.21328.55628.36827.52229.17530.66629.07729.14128.95930.20131.32428.58528.41927.20229.96731.03730.65529.56131.07232.44231.51231.31132.26233.41331.730

98.713102.855104.259105.030106.264104.326105.009105.101104.453105.927106.141106.583107.771107.211105.635105.998105.924104.948105.005105.001106.955107.035106.824107.500108.417108.372108.816105.914105.581105.870105.686104.057103.741103.710106.318106.605105.938106.204108.108108.627105.063104.479105.236105.482102.997

1.001.001.001.001.001.001.001.001.001.001.001.001.001.001.001.001.001.001.001.001.001.001.001.001.001.001.001.001.001.001.001.001.001.001.001.001.001.001.001.001.001.001.O01.001.00

44.7929.7234.2336.1940.2633.0331.5230.6928.3629.5729.0727.6532.0625.0226.5523.3323.9827.2618.3724.8120.0222.5619.2917.7223.7019.4021.1518.2316.8416.5513.8416.5012.4811.9316.3817.5316.5814.9816.9839.3815.5015.0117.0418.3715.31

LLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLL

ONCCONCCONCCOCNCCOCONCCOCCCNCCOCCCNCCOCSNCCOC

CGCD1CD2CE1CE2CZNCACOCBCGCD1CD2NCACOCBCGOD1ND2NCACOCBCGOD1ND2NCACOCBCGCD1CD2CE1CE2CZNCACO

PHE LPHE LPHE LPHE LPHE LPHE LLEU LLEU LLEU LLEU LLEU LLEU LLEU LLEU LASN LASN LASN LASN LASN LASN LASN LASN LASN LASN LASN LASN LASN LASN LASN LASN LPHE LPHE LPHE LPHE LPHE LPHE LPHE LPHE LPHE LPHE LPHE LTYR LTYR LTYR LTYR L

135135135135135135136136136136136136136136137137137137137137137137138138138138138138138138139139139139139139139139139139139140140140140

-6.719-6.530-7.604-7.221-8.312-8.121-3.795-2.784-1.633-1.013-2.528-3.800-4.513-3.447-1.385-0.4210.8940.972-1.084-2.092-2.866-2.0971.9323.2653.9284.3323.2372.9711.8634.0084.0734.6916.0096.3163.7273.2183.9312.0043.4901.5302.2786.8038.0858.4378.305

30.78429.42931.26328.53430.38329.00831.79432.55832.34731.27131.93731.92930.58332.08533.36333.20433.96135.03233.52332.42332.66831.26333.34833.91134.49535.64634.91334.22533.81234.07733.66534.06433.35532.41733.80032.37731.43432.00430.13930.69729.75333.84733.24033.74734.940

102.083102.170101.147101.341100.294100.399105.502106.211105.252105.214107.580108.451108.271109.904104.444103.397103.467104.011102.061101.574100.681102.196102.874102.768104.025104.061101.603100.280100.00699.461105.062106.294106.496105.788107.512107.633108.325107.061108.459107.197107.894107.430107.797109.186109.476

12.4412.7114.3716.7319.4521.6618.7717.2918.0320.8215.9017.8128.8011.2215.3715.7820.9624.0514.2615.0927.5222.7422.9819.9021.4120.4217.2521.5429.6231.9520.6218.0418.2820.3018.1920.4817.9317.2411.1116.6618.8921.0020.9522.5121.26

LLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLL

CCCCCCNCCOCCCCNCCOCCONNCCOCCONNCCOCCCCCCCNCCO

CBCGCD1CD2CE1CE2CZOHNCACOCBCGCDNCACOCBCGCDCENZNCACOCBCGOD1OD2NCACOCBCG1CG2CD1NCACOCB

TYR LTYR LTYR LTYR LTYR LTYR LTYR LTYR LPRO LPRO LPRO LPRO LPRO LPRO LPRO LLYS LLYS LLYS LLYS LLYS LLYS LLYS LLYS LLYS LASP LASP LASP LASP LASP LASP LASP LASP LILE LILE LILE LILE LILE LILE LILE LILE LASN LASN LASN LASN LASN L

140140140140140140140140141141141141141141141142142142142142142142142142143143143143143143143143144144144144144144144144145145145145145

9.21510.46111.31410.71912.37611.79712.61513.6848.8679.0727.8006.7059.8879.4229.3067.9576.8035.8524.7307.2917.8718.3649.1329.8406.2865.3914.2154.3516.1927.5748.5497.6603.0181.8550.7330.7241.4480.4560.9780.324-0.164-1.252-2.531-2.530-1.031

33.61232.81833.23331.60732.48130.82331.29030.52732.85531.39930.59531.15331.05432.05433.34429.28128.39028.20627.74327.01126.34124.90524.42523.11828.54028.28229.25230.47228.30127.68928.45226.44828.69929.56728.77327.53029.99331.14328.81431.86129.49328.79329.54130.76028.854

106.810107.134108.144106.502108.535106.901107.930108.384110.084109.974109.882109.928111.227112.197111.403109.762109.525110.707110.528109.176110.401110.124111.369111.175111.908113.048113.125113.035114.353114.178113.962114.240113.301113.387114.084114.087111.951111.976111.199110.617114.744115.442115.032114.907116.956

20.1221.2411.9319.6112.0511.8616.0120.6022.9123.1722.6422.6622.8725.5521.8122.2222.0720.2519.4324.4530.5938.6847.9668.0122.5120.7523.0824.4319.8627.4727.5035.1122.1321.6522.3925.8823.7320.9121.0223.8223.5029.0628.2729.9031.88

LLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLL

CCCCCCCONCCOCCCNCCOCCCCNNCCOCCOONCCOCCCCNCCOC

CGOD1ND2NCACOCBCG1CG2NCACOCBCGCDCENZNCACOCBCGCD1CD2NE1CE2CE3CZ2CZ3CH2NCACOCBCGCDCENZNCAC

ASN LASN LASN LVAL LVAL LVAL LVAL LVAL LVAL LVAL LLYS LLYS LLYS LLYS LLYS LLYS LLYS LLYS LLYS LTRP LTRP LTRP LTRP LTRP LTRP LTRP LTRP LTRP LTRP LTRP LTRP LTRP LTRP LLYS LLYS LLYS LLYS LLYS LLYS LLYS LLYS LLYS LILE LILE LILE L

145145145146146146146146146146147147147147147147147147147148148148148148148148148148148148148148148149149149149149149149149149150150150

-1.901-2.445-2.029-3.595-4.855-5.892-5.903-5.275-6.686-4.293-6.713-7.780-9.099-9.153-7.504-8.480-8.242-6.825-6.704-10.139-11.445-12.362-12.325-12.122-11.490-10.513-11.855-10.281-11.087-12.756-11.205-12.884-12.106-13.174-14.124-15.427-15.431-13.675-12.456-11.972-10.853-10.191-16.534-17.842-18.603

27.85728.19226.62728.79629.39128.97827.83828.86229.33229.45429.93229.64730.15131.25330.40230.10431.03730.89131.81729.32829.78530.18129.55928.65728.42227.48729.08527.54028.51330.11128.94330.54229.95531.21531.63631.91732.43132.90932.71234.03833.75935.02231.56331.80832.519

117.722118.780117.201114.797114.379115.396115.829112.986112.602111.948115.788116.732116.083115.542118.034119.109120.294120.876122.085116.116115.629116.806117.838114.890113.546113.208112.337111.832111.284112.040109.950110.716109.676116.623117.655116.932115.803118.375119.265119.890120.883121.349117.575116.995118.121

50.4764.1346.8226.8524.0121.8525.2822.1020.9229.4020.9823.4120.2917.7919.8134.9750.2556.3759.8020.1718.9521.2120.5915.8821.7416.6522.1522.2421.6514.2524.1320.2919.0322.8921.9422.0225.8822.5029.4136.1747.7958.0221.8519.4220.57

LLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLL

CONNCCOCCCNCCOCCCCNNCCOCCCCNCCCCCNCCOCCCCNNCC

OCBCG1CG2CD1NCACOCBCGOD1OD2NCACONCACOCBOGNCACOCBCGCDOE1OE2NCACOCBCGCDNECZNH1NH2NCA

ILE LILE LILE LILE LILE LASP LASP LASP LASP LASP LASP LASP LASP LGLY LGLY LGLY LGLY LSER LSER LSER LSER LSER LSER LGLU LGLU LGLU LGLU LGLU LGLU LGLU LGLU LGLU LARG LARG LARG LARG LARG LARG LARG LARG LARG LARG LARG LGLN LGLN L

150150150150150151151151151151151151151152152152152153153153153153153154154154154154154154154154155155155155155155155155155155155156156

-18.735-18.527-17.835-20.013-18.484-19.030-19.715-18.815-19.304-21.059-22.132-21.968-23.152-17.493-16.617-16.141-15.242-16.732-16.307-15.417-15.757-17.505-18.196-14.283-13.380-14.031-14.753-12.091-11.053-9.769-9.576-8.966-13.793-14.309-13.115-12.374-15.183-16.380-17.336-18.612-19.691-19.685-20.780-12.935-11.788

31.98230.51629.86830.80928.53533.73434.55934.70134.78933.89434.12935.05533.41634.68534.84533.60233.68832.45831.20930.39130.16130.36031.00629.94229.14127.82627.17528.87928.08427.92728.67927.06127.43526.18925.40625.87626.41927.23126.43827.11826.76225.71127.48224.22123.395

119.232116.639115.414116.281114.955117.831118.815120.052121.189119.175118.102117.272118.110119.850120.990121.724122.577121.438122.065121.122119.960122.471123.519121.643120.842120.432121.200121.635120.877121.683122.656121.335119.196118.675118.252117.405117.448117.799118.698118.747118.062117.260118.185118.829118.478

22.0517.6615.3915.455.5020.4920.9424.1224.2519.5925.6227.3231.2419.0223.5128.4132.8428.8529.0328.9726.3925.2330.7228.1231.3331.4835.2932.7840.8443.4247.1152.4128.4530.9132.1632.6628.5237.9231.3833.6517.4127.6825.1034.5235.80

LLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLL

OCCCCNCCOCCOONCCONCCOCONCCOCCCOONCCOCCCNCNNNC

COCBCGCDOE1NE2NCACOCBCGOD1ND2NCACONCACOCBCG1CG2NCACOCBCGCD1CD2NCACOCBCGOD1ND2NCAC

GLN LGLN LGLN LGLN LGLN LGLN LGLN LASN LASN LASN LASN LASN LASN LASN LASN LGLY LGLY LGLY LGLY LVAL LVAL LVAL LVAL LVAL LVAL LVAL LLEU LLEU LLEU LLEU LLEU LLEU LLEU LLEU LASN LASN LASN LASN LASN LASN LASN LASN LSER LSER LSER L

156156156156156156156157157157157157157157157158158158158159159159159159159159160160160160160160160160161161161161161161161161162162162

-12.127-11.293-11.078-10.673-9.873-10.360-8.643-13.341-13.708-14.121-14.616-14.866-14.457-15.297-13.175-13.987-14.353-13.389-13.795-12.136-11.148-10.165-9.706-10.376-9.279-11.327-9.892-8.948-7.885-8.238-9.658-8.866-9.801-8.126-6.625-5.543-4.602-4.409-4.759-5.511-6.298-5.232-4.045-3.099-2.031

22.21021.74922.90624.01023.50222.68523.98121.69820.53920.89021.99319.81219.00718.30919.08919.92220.11821.03521.66821.11421.95921.10120.08022.82023.65523.73721.46720.72821.76322.82420.23319.40018.46120.32121.45522.38721.75220.53822.71723.65124.47623.53922.55722.02923.129

117.605116.805119.743120.664121.845122.634121.977117.723116.913115.474115.235117.563118.785119.355119.191114.559113.154112.359111.391112.781112.106111.316111.799113.140112.436113.878110.073109.219108.832108.320107.946106.916106.149105.949109.089108.800107.801107.838110.086111.029110.607112.311106.886105.898105.737

36.4339.5633.2047.0357.6672.7163.1638.1738.1535.0134.0843.2657.3174.4054.4632.0126.6226.1326.9622.2323.7125.3734.9519.6726.3016.3629.0829.4424.7925.2729.9341.0238.9953.3221.1119.4918.6921.5519.3112.6721.5127.9617.6620.3220.31

LLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLL

COCCCONNCCOCCONNCCONCCOCCCNCCOCCCCNCCOCCONNCC

OCBOGNCACOCBCGCD1CD2NE1CE2CE3CZ2CZ3CH2NCACOCBOG1CG2NCACOCBCGOD1OD2NCACOCBCGCDOE1NE2NCACO

SER LSER LSER LTRP LTRP LTRP LTRP LTRP LTRP LTRP LTRP LTRP LTRP LTRP LTRP LTRP LTRP LTHR LTHR LTHR LTHR LTHR LTHR LTHR LASP LASP LASP LASP LASP LASP LASP LASP LGLN LGLN LGLN LGLN LGLN LGLN LGLN LGLN LGLN LASP LASP LASP LASP L

162162162163163163163163163163163163163163163163163164164164164164164164165165165165165165165165166166166166166166166166166167167167167

-2.347-3.766-2.842-0.7760.3201.1271.3251.2310.5440.495-0.167-0.199-0.614-0.463-1.350-1.199-1.6291.6002.4123.8714.2632.3672.7670.9784.6646.0956.5905.8506.6996.3095.8826.4527.8488.4158.3338.6049.84510.44211.70412.50411.9007.9207.7689.16810.151

24.34421.77121.09622.71123.66223.38022.21723.48523.65724.78622.65124.56023.25921.30222.56920.59521.24324.41624.19224.01824.32425.37826.59825.56223.50523.39724.82025.63322.43220.98620.38420.46025.08926.42426.80626.01426.45827.87527.93626.97429.05028.03628.52028.64929.093

105.761104.569103.721105.539105.444104.181103.821106.662108.029108.763108.791109.945109.977108.575110.961109.565110.738103.506102.285102.682103.801101.286101.961100.694101.739101.939101.584101.007100.915101.155100.158102.298101.885101.625100.15699.290102.164102.139102.959102.995103.62899.87498.52397.86498.482

20.4819.3630.6422.9617.2016.7520.5513.3322.8019.3226.7130.7726.8632.1326.9731.6837.5519.4918.4019.8118.4816.1022.6920.8222.9623.1918.8818.6030.0140.6452.9738.5313.8112.2112.8116.6512.3512.7516.6422.9515.1615.5417.0617.6917.79

LLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLL

OCONCCOCCCCNCCCCCNCCOCOCNCCOCCOONCCOCCCONNCCO

CBCGOD1OD2NCACOCBOGNCACOCBCGCDCENZNCACOCBCGOD1OD2NCACOCBOGNCACOCBOG1CG2NCACOCB

ASP LASP LASP LASP LSER LSER LSER LSER LSER LSER LLYS LLYS LLYS LLYS LLYS LLYS LLYS LLYS LLYS LASP LASP LASP LASP LASP LASP LASP LASP LSER LSER LSER LSER LSER LSER LTHR LTHR LTHR LTHR LTHR LTHR LTHR LTYR LTYR LTYR LTYR LTYR L

167167167167168168168168168168169169169169169169169169169170170170170170170170170171171171171171171172172172172172172172173173173173173

7.0956.7855.7507.5979.19110.38510.85811.99910.13310.01110.00510.39710.61611.6109.3199.2398.1168.2447.2589.6999.91510.24010.3458.7197.4207.4576.36210.43710.8549.90510.33212.26013.0928.6297.6346.8246.9506.6195.9047.3825.9595.0913.6663.4425.366

29.90830.35629.91731.12728.25728.29029.65929.78227.46526.11730.65731.98932.92233.62332.57431.82132.33331.76332.40332.97233.91433.30934.01834.87434.18033.00634.85931.98031.27231.41631.27731.71531.63931.62731.74530.42829.53432.89632.66034.27830.37429.26029.79931.01828.683

98.50897.11996.60296.51496.60795.76195.32294.87994.48094.89295.39894.95896.11496.14594.02192.66791.77390.35689.41497.08398.17699.528100.53598.26998.76999.21398.75399.555100.771101.967103.131101.193100.049101.661102.747102.837101.988102.488101.251102.381103.849104.100104.107104.327105.488

13.5322.4624.4325.8021.9324.5723.4725.3017.8438.0520.4919.3220.1019.9921.2930.1744.0157.3870.7723.1620.4322.4924.0623.5228.5928.2532.0222.3019.5418.9120.8416.8622.6417.1917.2715.1213.2515.9624.2910.4314.8913.9815.9911.8312.06

LLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLL

CCOONCCOCONCCOCCCCNNCCOCCOONCCOCONCCOCOCNCCOC

CGCD1CD2CE1CE2CZOHNCACOCBOGNCACOCBCGSDCENCACOCBOGNCACOCBOGNCACOCBOG1CG2NCACOCB

TYR LTYR LTYR LTYR LTYR LTYR LTYR LSER LSER LSER LSER LSER LSER LMET LMET LMET LMET LMET LMET LMET LMET LSER LSER LSER LSER LSER LSER LSER LSER LSER LSER LSER LSER LTHR LTHR LTHR LTHR LTHR LTHR LTHR LLEU LLEU LLEU LLEU LLEU L

173173173173173173173174174174174174174175175175175175175175175176176176176176176177177177177177177178178178178178178178179179179179179

6.7327.8276.9379.0928.2169.27610.5302.7061.2810.4650.9240.7701.300-0.753-1.562-3.020-3.417-1.381-2.422-2.089-3.279-3.803-5.268-5.934-5.486-5.673-7.084-6.986-7.641-9.113-9.583-7.412-7.994-9.823-11.227-12.029-11.728-11.483-10.737-12.952-13.001-13.874-15.197-15.884-14.157

28.07628.83226.74928.26926.17426.95126.36128.89229.27628.19927.06529.44330.63228.53527.53327.78128.94927.71126.93027.30126.11726.69926.83026.20225.14626.02025.98426.81826.17026.21927.27926.99226.37725.08925.06324.57723.48724.06424.44324.04925.38024.95824.47025.24326.132

105.588106.026105.215106.067105.287105.713105.841103.891103.906104.605104.737102.491101.906105.046105.762105.431105.198107.296108.210109.942110.822105.418105.196106.436106.909103.982103.817106.972108.128107.753107.371109.379110.518107.862107.512108.721109.262106.371105.195106.014109.168110.279109.628108.957111.207

19.9518.4412.6328.5320.2420.8231.8817.0814.7915.2218.0516.5116.1916.1913.0114.5617.5013.6111.5019.8419.3712.1412.4314.5213.6411.9316.8614.3514.3816.2019.7210.6318.2818.7219.8019.4519.4417.8120.8620.6316.5619.5019.7819.6818.74

LLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLL

CCCCCCONCCOCONCCOCCSCNCCOCONCCOCONCCOCOCNCCOC

CGCD1CD2NCACOCBOG1CG2NCACOCBCGCD1CD2NCACOCBOG1CG2NCACOCBCGCDCENZNCACOCBCGOD1OD2NCAC

LEU LLEU LLEU LTHR LTHR LTHR LTHR LTHR LTHR LTHR LLEU LLEU LLEU LLEU LLEU LLEU LLEU LLEU LTHR LTHR LTHR LTHR LTHR LTHR LTHR LLYS LLYS LLYS LLYS LLYS LLYS LLYS LLYS LLYS LASP LASP LASP LASP LASP LASP LASP LASP LGLU LGLU LGLU L

179179179180180180180180180180181181181181181181181181182182182182182182182183183183183183183183183183184184184184184184184184185185185

-15.233-14.778-15.411-15.558-16.778-17.911-17.733-16.510-15.554-17.819-19.061-20.256-21.404-21.281-20.618-19.507-19.910-19.133-22.537-23.734-24.299-23.964-24.819-25.233-24.250-25.161-25.817-26.611-26.590-26.777-27.654-28.739-29.711-29.183-27.335-28.132-27.275-27.641-28.909-30.029-30.432-30.492-26.126-25.239-24.726

25.97124.89927.33023.20922.72822.55122.00721.43721.72020.90223.10923.07922.59522.49124.48625.35226.78624.73522.34221.98323.32524.34021.22622.05619.97423.33224.53825.16126.36724.22225.40024.91226.00526.87924.32024.78725.43126.48023.61323.16423.97122.01724.82325.40626.743

112.315113.287113.049109.836109.226110.243111.335108.450107.419107.799109.883110.722109.874108.654111.158111.691111.792113.056110.524109.771109.392110.009110.648111.724111.210108.377107.953109.111109.326106.814106.442105.465105.066103.976109.825110.967112.047112.605111.550110.615109.744110.752112.341113.396112.905

19.1722.8513.6116.3922.4722.4022.2424.6928.7025.6025.7623.8022.4027.5420.9921.1118.2635.9321.4921.6618.6717.0720.5419.0819.2322.5327.9328.4028.7524.8538.6851.4661.2265.8828.4230.2927.7826.3632.4147.0350.3857.3926.3422.3321.73

LLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLL

CCCNCCOCOCNCCOCCCCNCCOCOCNCCOCCCCNNCCOCCOONCC

OCBCGCDOE1OE2NCACOCBCGCD1CD2CE1CE2CZOHNCACOCBCGCDOE1OE2NCACOCBCGCDNECZNH1NH2NCAC0CBCGND1

GLU LGLU LGLU LGLU LGLU LGLU LTYR LTYR LTYR LTYR LTYR LTYR LTYR LTYR LTYR LTYR LTYR LTYR LGLU LGLU LGLU LGLU LGLU LGLU LGLU LGLU LGLU LARG LARG LARG LARG LARG LARG LARG LARG LARG LARG LARG LHIS LHIS LHIS LHIS LHIS LHIS LHIS L

185185185185185185186186186186186186186186186186186186187187187187187187187187187188188188188188188188188188188188189189189189189189189

-24.747-24.076-22.917-23.294-24.490-22.395-24.296-23.812-24.884-24.594-23.443-23.034-21.856-23.841-21.492-23.480-22.298-21.907-26.145-27.213-27.671-28.433-28.403-28.097-29.007-28.892-29.806-27.167-27.486-26.523-26.692-27.455-28.633-28.685-27.676-27.839-28.973-26.897-25.492-24.505-24.228-24.560-23.256-23.474-23.498

27.75424.42925.08225.43825.39225.77926.77228.00329.09630.25127.76929.03729.71329.58930.92830.80031.45832.65728.73229.74430.15631.11229.30429.58728.85829.17827.96629.46229.79330.77131.20328.52727.61026.56825.52324.35724.06023.43831.14932.05333.19933.13131.23930.23430.610

113.623113.729114.549116.017116.384116.802111.637111.033111.135111.475109.565108.828109.171107.835108.541107.198107.569107.007110.882110.959112.367112.532110.087108.603107.603106.397107.994113.385114.769115.368116.517115.636115.410116.464116.368115.741115.106115.816114.613115.171114.218113.040115.485116.589117.912

19.7422.6923.7024.9427.9127.1720.5920.7221.3219.9721.8820.1316.1013.4722.6021.6617.3826.1226.5828.7926.9628.1829.1538.8954.7354.7557.1925.6023.8626.9532.9425.2918.4920.6622.0831.0521.5120.6427.1423.8524.2620.6321.8223.4318.19

LLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLL

OCCCOONCCOCCCCCCCONCCOCCCOONCCOCCCNCNNNCCOCCN

CD2CE1NE2NCACOCBCGOD1ND2NCACOCBOGNCACOCBCGCD1CD2CE1CE2CZOHNCACOCBOG1CG2NCACOCBSGNCAC

HIS LHIS LHIS LASN LASN LASN LASN LASN LASN LASN LASN LSER LSER LSER LSER LSER LSER LTYR LTYR LTYR LTYR LTYR LTYR LTYR LTYR LTYR LTYR LTYR LTYR LTHR LTHR LTHR LTHR LTHR LTHR LTHR LCYS LCYS LCYS LCYS LCYS LCYS LGLU LGLU LGLU L

189189189190190190190190190190190191191191191191191192192192192192192192192192192192192193193193193193193193194194194194194194195195195

-23.717-23.754-23.897-23.636-23.396-21.949-21.665-24.129-24.115-24.446-23.741-21.084-19.696-18.738-18.689-19.320-18.092-17.976-17.029-15.622-15.425-17.436-18.679-19.962-18.581-21.146-19.753-21.015-22.121-14.676-13.354-12.233-12.326-13.187-14.157-11.784-11.215-9.983-8.897-8.706-9.561-8.068-8.283-7.182-5.844

28.90429.56128.50434.25035.39035.83436.24036.59337.78637.65738.95635.79836.27935.12334.21937.05637.70735.16434.10234.72935.69133.47032.62533.18531.29132.40130.49331.07030.28734.19034.77433.75832.69835.49536.55336.00934.10833.31834.15435.29433.39132.43433.63934.33433.609

116.570118.670117.885114.735113.884113.572112.473114.472113.535112.341114.065114.568114.426114.233115.065115.696115.570113.130112.825112.770112.063111.492111.641111.509112.002111.748112.245112.115112.355113.545113.604113.480114.063114.971115.064115.147112.690112.457113.238112.848110.919110.661114.320115.024114.798

16.2813.0615.1324.8926.5725.0718.6533.0744.2256.4338.6624.9624.1523.4425.3320.6434.9520.4720.9722.1924.1017.6223.2222.5918.1918.7521.0522.7119.4022.3624.4124.1027.3723.1621.7524.7522.5426.5826.1924.2324.9442.8124.4829.5930.32

LLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLL

CCNNCCOCCONNCCOCONCCOCCCCCCCONCCOCOCNCCOCSNCC

OCBCGCDOE1OE2NCACOCBNCACOCBOG1CG2NCACOCBCGND1CD2CE1NE2NCACOCBCGCDCENZNCACOCBOG1CG2N

GLU LGLU LGLU LGLU LGLU LGLU LALA LALA LALA LALA LALA LTHR LTHR LTHR LTHR LTHR LTHR LTHR LHIS LHIS LHIS LHIS LHIS LHIS LHIS LHIS LHIS LHIS LLYS LLYS LLYS LLYS LLYS LLYS LLYS LLYS LLYS LTHR LTHR LTHR LTHR LTHR LTHR LTHR LSER L

195195195195195195196196196196196197197197197197197197198198198198198198198198198198199199199199199199199199199200200200200200200200201

-5.736-7.426-8.541-8.662-7.813-9.588-4.832-3.507-2.409-2.284-3.153-1.607-0.4730.7590.832-0.477-0.216-1.8271.7112.9194.0363.7882.7193.8644.7894.2595.7065.4105.2686.3916.3366.7847.7079.03410.14411.54812.5535.7835.7854.9164.8315.4304.2836.6424.240

32.40934.40035.34335.48134.88936.17634.35133.78934.42035.64233.99133.59234.12533.58332.42033.71132.31034.04634.46934.14734.91535.87934.65134.34035.29233.17934.72933.44834.49935.17936.68437.42934.63335.29634.71735.18334.72537.13538.55439.44540.65138.78337.98238.34738.842

115.054116.545116.918118.422119.126118.878114.356114.084114.908114.929112.624115.568116.305115.564115.140117.796117.927118.406115.370114.605115.289116.009113.168112.254111.880111.670111.110110.968115.058115.711115.519116.387115.116115.576114.743115.205114.206114.393114.042114.890114.626112.541112.176111.650115.875

32.3430.1736.2440.4137.6445.5829.6428.0928.5430.5629.6829.3932.7531.1228.1934.2037.7533.9230.7327.7428.6626.2824.9723.6026.7423.1722.1817.9128.4630.4530.5634.5031.2233.0231.7526.5735.9330.7430.3936.7540.2230.6334.1726.3342.72

LLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLL

OCCCOONCCOCNCCOCOCNCCOCCNCCNNCCOCCCCNNCCOCOCN

CACOCBOGNCACOCBOG1CG2NCACOCBOGNCACOCBCGCDNCACOCBCG1CG2CD1NCACOCBCG1CG2NCACOCB

SER LSER LSER LSER LSER LTHR LTHR LTHR LTHR LTHR LTHR LTHR LSER LSER LSER LSER LSER LSER LPRO LPRO LPRO LPRO LPRO LPRO LPRO LILE LILE LILE LILE LILE LILE LILE LILE LVAL LVAL LVAL LVAL LVAL LVAL LVAL LLYS LLYS LLYS LLYS LLYS L

201201201201201202202202202202202202203203203203203203204204204204204204204205205205205205205205205206206206206206206206207207207207207

3.4442.8552.1262.3281.7113.1602.6521.0970.4683.1474.5173.0650.494-0.965-1.454-0.916-1.298-0.510-2.522-3.014-3.502-3.898-4.137-4.723-3.435-3.460-3.986-5.428-5.641-3.219-1.814-3.974-0.939-6.396-7.813-8.582-8.531-8.485-9.979-7.782-9.259-10.088-11.472-11.585-9.560

39.60138.72837.75640.36441.22339.07338.34438.31137.33239.04139.44538.10339.39939.54438.95839.27941.01341.64238.15137.55338.50639.61336.63537.43837.84938.04338.79638.23937.01338.43239.07338.93838.66639.13938.75939.10240.23439.49539.14439.06038.12738.41037.83236.73737.756

116.831117.916117.644116.130117.077119.157120.314120.322120.756121.586121.400122.770119.845119.772118.442117.377119.794118.792118.477117.233116.165116.453117.715118.867119.599114.921113.780113.757113.784112.471112.503111.248111.290113.730113.789112.524112.081115.011115.107116.324111.900110.716111.032111.566109.450

43.9147.5750.7043.2348.6252.0556.4856.1556.7959.0062.7563.2854.9752.6249.4248.6954.2858.4147.3442.5639.2033.5044.2743.0948.0037.4132.9130.6229.6334.5531.3424.0142.4425.8924.4022.4426.8420.8025.9328.4023.3621.6523.7627.9023.08

LLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLL

CCOCONCCOCOCNCCOCONCCOCCCNCCOCCCCNCCOCCCNCCOC

原子原子原子原子原子原子原子原子原子原子原子原子原子原子原子原子原子原子原子原子原子原子原子原子原子原子原子原子原子原子原子原子原子原子原子原子原子原子原子原子原子TER原子原子原子

CGCDCENZNCACOCBOGNCACOCBCGCD1CD2CE1CE2CZNCACOCBCGOD1ND2NCACOCBCGCDNECZNH1NH2OXTNCAC

LYS LLYS LLYS LLYS LSER LSER LSER LSER LSER LSER LPHE LPHE LPHE LPHE LPHE LPHE LPHE LPHE LPHE LPHE LPHE LASN LASN LASN LASN LASN LASN LASN LASN LARG LARG LARG LARG LARG LARG LARG LARG LARG LARG LARG LARG LARG LGLU HGLU HGLU H

207207207207208208208208208208209209209209209209209209209209209210210210210210210210210211211211211211211211211211211211211211111

-8.259-8.452-7.059-7.248-12.515-13.865-14.875-14.619-14.363-13.384-16.051-17.173-18.428-18.387-17.269-17.620-18.955-16.606-19.254-16.897-18.229-19.522-20.809-21.715-21.804-21.424-20.647-20.232-20.427-22.349-23.225-24.255-24.483-23.897-24.800-25.278-25.888-27.142-27.949-27.568-24.79613.63413.49712.992

38.39739.81840.48141.83738.55338.07138.50639.40738.72238.71237.88038.34238.04937.25337.66436.19835.76535.24134.40433.89533.46438.73738.49737.86838.32639.78940.35839.62441.67336.77936.07637.08837.08534.87433.98532.77933.19633.60533.63134.04837.88716.01915.89714.523

109.002108.444108.245107.672110.696111.044110.050109.269112.364113.361110.105109.303110.129111.055107.939108.000108.039108.000108.072108.027108.063109.814110.471109.438108.302110.987112.131113.028112.111109.810108.891108.362107.129109.605108.728109.472110.725110.849109.786112.027109.15873.39674.87975.281

32.2539.9645.6449.0824.3825.8023.1727.4025.6044.5122.2520.5022.4824.5816.1326.9426.8431.1527.0021.0019.7429.5332.5333.0737.8133.3141.9753.1348.3334.5036.4243.2047.0932.1123.3919.9938.2844.6748.2446.3143.5837.0537.2632.62

LLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLHHH

CCCNNCCOCONCCOCCCCCCCNCCOCCONNCCOCCCNCNNONCC

OCBCGCDOE1OE2NCACOCBCG1CG2NCACOCBNCACOCBCGCD1CD2NCACOCBCG1CG2NCACOCBCGCDOE1OE2NCAC

GLU HGLU HGLU HGLU HGLU HGLU HVAL HVAL HVAL HVAL HVAL HVAL HVAL HALA HALA HALA HALA HALA HLEU HLEU HLEU HLEU HLEU HLEU HLEU HLEU HVAL HVAL HVAL HVAL HVAL HVAL HVAL HGLU HGLU HGLU HGLU HGLU HGLU HGLU HGLU HGLU HSER HSER HSER H

111111222222233333444444445555555666666666777

12.10312.53711.93011.58511.48811.41713.54813.12211.81711.67014.10113.46715.43910.8659.5939.0899.1858.5498.6098.0616.6896.5848.91610.38411.15110.4465.6394.2903.5133.0953.5052.0924.2043.2822.5901.0800.5352.9484.4985.1214.6526.1690.426-1.051-1.494

13.97216.96916.63517.88917.80718.95813.97312.65312.85713.77812.06110.84611.70011.99412.07310.6619.69812.84510.5389.2879.65810.5148.7668.4748.0007.3669.0059.3648.1557.2629.99010.28211.2638.1436.9977.1018.1876.7786.6437.9759.0357.9565.9545.9574.639

74.64475.41176.75077.55378.80576.92276.35576.83377.55778.35977.86778.51977.20577.29077.97578.37377.59377.05279.61280.13780.67881.59081.30280.83782.07179.75080.17680.62081.16780.39779.46479.92578.98982.47483.07483.00582.93084.53984.82585.12984.65285.93082.99383.00883.623

31.0539.0756.6873.8477.8678.3830.9725.2725.4528.5221.4920.6823.1525.4028.2926.9729.4827.6924.2220.8922.7627.0722.5517.6617.3923.9224.4020.4320.6923.2617.3712.6516.0818.2321.0224.6424.7223.5122.4024.0022.5120.1425.3524.7123.70

HHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH

OCCCOONCCOCCCNCCOCNCCOCCCCNCCOCCCNCCOCCCOONCC

OCBOGNCACONCACONCACONCACOCBCGCD1CD2NCACOCBCG1CG2NCACOCBCGCDCENZNCACOCBCG

SER HSER HSER HGLY HGLY HGLY HGLY HGLY HGLY HGLY HGLY HGLY HGLY HGLY HGLY HLEU HLEU HLEU HLEU HLEU HLEU HLEU HLEU HVAL HVAL HVAL HVAL HVAL HVAL HVAL HLYS HLYS HLYS HLYS HLYS HLYS HLYS HLYS HLYS HPRO HPRO HPRO HPRO HPRO HPRO H

7778888999910101010111111111111111112121212121212131313131313131313141414141414

-0.669-1.625-1.219-2.793-3.309-3.483-3.994-3.071-3.267-4.736-5.554-5.050-6.399-6.617-5.670-7.894-8.248-8.468-9.134-9.553-10.211-9.387-11.577-7.979-8.140-8.342-7.779-6.873-5.599-7.045-9.176-9.363-8.219-7.512-10.696-11.898-13.189-14.387-14.447-8.006-6.935-7.158-8.300-7.162-7.812

3.7506.1375.1094.5353.3063.2392.2424.2564.1064.3664.7424.1864.4063.6063.1353.4182.7041.2170.8593.2752.5932.6383.3190.362-1.062-1.688-1.243-1.668-1.392-3.187-2.723-3.342-4.272-4.781-4.153-3.328-3.961-3.251-3.378-4.494-5.398-6.767-7.224-5.504-4.191

83.87081.60280.73383.92684.47985.97386.48586.71488.13388.50587.65889.77190.22491.47492.10791.83093.05092.76291.79093.61694.82996.06995.07693.64193.40894.74795.72292.69393.53992.48294.82696.11596.47495.61896.14595.77396.27995.69094.19097.76398.19197.49997.38299.686100.033

23.7924.3129.6724.5726.4027.6732.6826.7030.2631.5334.3926.6424.0628.4629.6527.8126.6829.7931.9727.4630.7821.3926.6131.5131.1729.1529.5632.0028.6329.0028.7031.5630.3833.1133.1641.9151.5465.1458.2528.4727.8130.7333.0027.1525.33

HHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH

OCONCCONCCONCCONCCOCCCCNCCOCCCNCCOCCCCNNCCOCC

CDNCACONCACONCACOCBOGNCACOCBCGCD1CD2NCACOCBCGCDCENZNCACOCBCGCD1CD2NCACOCB

PRO HGLY HGLY HGLY HGLY HGLY HGLY HGLY HGLY HSER HSER HSER HSER HSER HSER HLEU HLEU HLEU HLEU HLEU HLEU HLEU HLEU HLYS HLYS HLYS HLYS HLYS HLYS HLYS HLYS HLYS HLEU HLEU HLEU HLEU HLEU HLEU HLEU HLEU HSER HSER HSER HSER HSER H

141515151516161616171717171717181818181818181819191919191919191920202020202020202121212121

-8.684-6.077-6.149-6.402-6.348-6.658-6.924-5.678-4.555-5.912-4.893-5.030-6.118-5.035-4.519-3.933-3.967-2.737-1.704-3.904-4.099-5.511-3.910-2.838-1.670-1.353-2.207-1.911-0.624-0.8770.4380.227-0.1200.3341.1191.8141.2770.7991.851-0.5381.0501.7492.6362.3530.748

-3.850-7.418-8.694-8.471-9.393-7.228-6.919-6.869-7.147-6.536-6.420-5.095-4.506-7.527-8.733-4.645-3.407-3.388-3.871-2.234-0.827-0.7180.228-2.822-2.786-1.349-0.617-3.507-3.721-4.632-5.139-5.854-0.9420.4170.431-0.5520.9000.7501.3061.5051.5581.7542.9783.9111.964

98.90197.08796.39894.92294.11494.54793.15992.27592.74091.00789.97089.24989.21088.92589.43388.63587.89286.97987.38488.88288.31187.71689.40285.78984.91584.57884.06283.59382.77181.55180.97179.67084.88184.58783.29382.96985.70787.14388.11987.26782.59581.35981.44082.19580.229

24.2331.5026.4331.3537.7730.4230.3630.4033.8227.0931.0133.1235.4929.4040.2329.1131.4028.0431.1236.0536.1332.1141.1223.4923.1526.4325.0624.4328.1627.1137.8750.8025.6323.0921.8923.5822.8023.0730.1726.0719.2922.0824.3027.2221.00

HHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH

CNCCONCCONCCOCONCCOCCCCNCC0CCCCNNCCOCCCCNCCOC

OGNCACOCBSGNCACOCBNCACOCBNCACOCBOGNCACONCACOCBCGCD1CD2CE1CE2CZNCACOCBOGCG2

SER HCYS HCYS HCYS HCYS HCYS HCYS HALA HALA HALA HALA HALA HALA HALA HALA HALA HALA HSER HSER HSER HSER HSER HSER HGLY HGLY HGLY HGLY HPHE HPHE HPHE HPHE HPHE HPHE HPHE HPHE HPHE HPHE HPHE HTHR HTHR HTHR HTHR HTHR HTHR HTHR H

212222222222222323232323242424242425252525252526262626272727272727272727272728282828282828

0.0113.6614.5714.9815.6465.8026.9924.5564.8556.1796.3063.7397.1338.4278.7418.3979.4809.4079.76111.00411.3838.5838.34411.67812.80714.15115.13914.19915.48215.29714.15215.96415.03515.27813.90514.41713.02813.27616.40016.30715.93716.77517.61017.83417.527

0.7612.9914.1254.3133.4373.8975.2495.4365.8216.5857.6636.7386.0736.7057.2706.6795.7048.4149.0229.89610.2429.88910.93510.21011.11110.47011.1769.1418.4267.0676.6228.3017.4916.1648.0735.4047.3296.0096.3585.0564.0133.3634.7275.7473.399

80.03080.60880.53679.09078.53281.42481.18878.48977.11477.07777.65576.54476.31876.29074.95073.92176.68774.94673.68073.85574.96773.20074.13272.76972.91173.08473.29473.02873.11272.47172.25074.59175.50475.78876.05876.61376.89377.17472.22571.57072.54973.12670.87169.90270.157

34.4321.9820.6421.2427.2621.0229.5817.7620.0023.2625.7217.8124.3625.2826.1327.3925.9824.1726.4726.4628.6227.4524.6922.5520.5424.3224.8921.9320.1421.3223.0020.3618.1210.1918.2015.9621.169.6720.9620.7422.2825.4917.3522.0221.93

HHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH

ONCCOCSNCCOCNCCOCNCCOCONCCONCCOCCCCCCCNCCOCOC

NCACOCBCGCD1CD2CE1CE2CZNCACOCBCG1CG2CD1NCACOCBOGNCACOCBCGCD1CD2CE1CE2CZOHNCACOCBNCAC

PHE HPHE HPHE HPHE HPHE HPHE HPHE HPHE HPHE HPHE HPHE HILE HILE HILE HILE HILE HILE HILE HILE HSER HSER HSER HSER HSER HSER HTYR HTYR HTYR HTYR HTYR HTYR HTYR HTYR HTYR HTYR HTYR HTYR HALA HALA HALA HALA HALA HMET HMET HMET H

292929292929292929292930303030303030303131313131313232323232323232323232323333333333343434

14.63614.09214.69815.02312.56811.82111.54711.33710.80210.58710.33014.87215.39316.75217.02715.48816.36914.06116.80217.54618.89018.98420.04119.87420.16917.88317.88617.15216.11517.31018.19818.20319.04219.02019.88219.85720.66617.69817.05715.99316.12318.05514.94913.87413.439

3.8542.9221.5341.0812.8082.0692.6810.7741.9960.0860.7040.847-0.520-0.688-1.775-1.222-0.396-1.412-1.1360.3770.2610.5030.2561.2060.7220.9521.2400.280-0.3022.6653.7934.1424.4875.1525.5055.8286.8500.140-0.6150.3941.624-1.001-0.1400.7000.188

72.73073.70773.82774.93773.47674.55175.78474.32876.75275.31676.51572.69972.75373.40373.90971.35070.42470.76869.18673.44374.00375.50876.08973.29171.96276.12477.54978.44178.07677.81877.29875.94378.15675.45777.67976.33075.86379.65180.69581.25281.10481.80681.86282.41683.758

20.1219.2420.3422.8818.9818.9417.2017.9320.2220.547.2022.0524.8022.0623.4923.2623.1032.1238.8318.2618.4518.6921.4614.5031.4518.0314.3315.0214.3713.7917.1614.5614.5617.4520.1823.4928.2314.4214.5114.3912.1712.6816.8416.3615.55

HHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH

NCCOCCCCCCCNCCOCCCCNCCOCONCCOCCCCCCCONCCOCNCC

OCBCGSDCENCACOCBOGNCACOCBCGCD1CD2NE1CE2CE3CZ2CZ3CH2NCACOCBCG1CG2NCACOCBCGCDNECZNH1NH2NCA

MET HMET HMET HMET HMET HSER HSER HSER HSER HSER HSER HTRP HTRP HTRP HTRP HTRP HTRP HTRP HTRP HTRP HTRP HTRP HTRP HTRP HTRP HVAL HVAL HVAL HVAL HVAL HVAL HVAL HARG HARG HARG HARG HARG HARG HARG HARG HARG HARG HARG HGLN HGLN H

343434343435353535353536363636363636363636363636363737373737373738383838383838383838383939

13.60112.65112.88713.10811.53312.79012.37411.09210.62013.45114.75510.5679.4489.97010.6118.2327.5037.7056.5056.8976.1445.8745.1774.9294.5829.66010.0938.8458.26911.24911.64812.4888.4927.2877.6308.6846.2826.7725.7896.2725.6884.6206.1326.7226.952

-0.9870.6971.2233.0143.6881.0530.6161.3062.2510.9920.3860.7711.3831.5980.7090.4670.323-0.6691.203-0.4300.6982.3651.3142.9812.4562.7773.1153.7704.6294.1804.5863.5633.3783.9534.7754.6322.8401.9380.730-0.154-1.319-1.693-2.0785.6876.530

84.08681.47480.07179.96880.66284.54685.87586.34885.72286.95186.72387.44088.15489.59090.21088.23186.88585.93786.34584.85685.07886.81784.26786.02284.74590.13891.48192.10191.49591.43692.88090.69393.31993.92395.14695.73494.30795.38695.62296.66196.94996.23997.94895.49496.674

13.1115.2414.0920.487.1816.9119.0418.3124.0414.3022.0012.0112.9518.2816.0114.7121.419.6718.0723.7417.044.9816.7419.8318.4619.2919.6419.1419.3220.6117.5017.1316.7715.9818.0416.6216.858.2111.1914.8922.7624.0623.1618.4822.51

HHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH

OCCSCNCCOCONCCOCCCCNCCCCCNCCOCCCNCCOCCCNCNNNC

COCBCGCDOE1NE2NCACOCBOG1CG2NCACOCBCGCDNCACOCBCGCDOE1OE2NCACOCBCGCDCENZNCACOCBCG

GLN HGLN HGLN HGLN HGLN HGLN HGLN HTHR HTHR HTHR HTHR HTHR HTHR HTHR HPRO HPRO HPRO HPRO HPRO HPRO HPRO HGLU HGLU HGLU HGLU HGLU HGLU HGLU HGLU HGLU HLYS HLYS HLYS HLYS HLYS HLYS HLYS HLYS HLYS HARG HARG HARG HARG HARG HARG H

393939393939394040404040404041414141414141424242424242424242434343434343434343444444444444

5.6814.5897.1357.5168.0127.4509.0695.8734.7594.1864.7805.2166.2095.7733.0222.4773.4433.4581.1290.7342.0884.2675.2126.4397.3335.6374.4413.8224.4242.7486.4287.5058.7559.7547.9387.3265.8725.1233.6898.7179.9179.8878.8169.8979.672

6.3986.7037.9938.85510.20610.79910.7095.9605.6956.9998.0834.8955.6583.5126.9138.1728.7789.9747.7546.5065.7907.9598.5089.1129.5767.4496.6875.7124.6356.0399.1339.7128.8819.39111.08712.21512.29912.59412.8337.6126.7786.2735.9605.5615.841

97.56097.10696.24297.44597.00396.08097.65798.79099.685100.217100.063100.892101.561100.514100.873101.383102.402102.614101.986101.085101.047103.020103.978103.280103.954104.982105.587104.591104.358104.027101.944101.126100.935100.407101.655100.938101.20999.921100.223101.318101.15199.70999.168102.080103.567

26.2229.4120.0814.7117.6922.7418.9425.0829.2833.5132.0231.2631.1325.7636.6636.8634.1931.1937.3840.4434.7933.5031.6130.0728.5435.5446.3659.4159.8263.0525.5224.3724.9622.8827.0934.7451.3551.9950.4625.0727.5127.1823.8630.7544.30

HHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH

COCCCONNCCOCOCNCCOCCCNCCOCCCOONCCOCCCCNNCCOCC

CDNECZNH1NH2NCACOCBCGCD1CD2NCACOCBCGCDOE1OE2NCACOCBCGCD1CD2NE1CE2CE3CZ2CZ3CH2NCACOCBCG1CG2NCA

ARG HARG HARG HARG HARG HLEU HLEU HLEU HLEU HLEU HLEU HLEU HLEU HGLU HGLU HGLU HGLU HGLU HGLU HGLU HGLU HGLU HTRP HTRP HTRP HTRP HTRP HTRP HTRP HTRP HTRP HTRP HTRP HTRP HTRP HTRP HVAL HVAL HVAL HVAL HVAL HVAL HVAL HALA HALA H

444444444445454545454545454646464646464646464747474747474747474747474747484848484848484949

10.83912.09713.09312.98514.23311.05711.18111.63712.51912.23811.74312.98110.84911.03711.39811.45010.46710.31110.1238.9558.1578.86112.58612.70811.76911.79214.18114.38614.23214.70814.42514.72814.98715.02115.28015.29310.9769.98010.3289.9668.6027.6118.05211.03411.346

6.4975.7555.8696.6845.2176.2345.7684.2873.9336.6078.0378.9678.0213.4652.0411.5711.7311.1891.5930.8460.1800.9231.0150.485-0.762-1.5840.092-0.878-0.609-2.240-1.758-2.771-3.087-4.120-4.440-4.929-0.857-1.935-2.961-4.116-1.279-2.301-0.607-2.548-3.493

104.317104.254105.139106.193104.92599.09597.72397.77998.55096.97896.59296.32495.33796.94096.91595.47894.75197.63599.11799.81799.090101.08095.07193.72893.67994.59293.50192.32490.97892.43290.24691.12193.52090.86493.25791.94592.61392.40091.31691.44292.03891.49893.27490.26389.194

61.8270.5263.4251.2741.3021.9923.7522.2021.3320.4626.1519.177.9521.9826.5821.1122.2128.6549.9862.4554.9476.6316.2717.0715.2718.7919.1716.798.7115.9415.3713.7319.4917.6511.7916.6416.4020.2717.2717.4921.3424.1524.2416.9617.77

HHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH

CNCNNNCCOCCCCNCCOCCCOONCCOCCCCNCCCCCNCCOCCCNC

COCBNCACOCBOGNCACOCBCG1CG2CD1NCACOCBOGNCACOCBOGNCACONCACONCACOCBCGOD1ND2

ALA HALA HALA HSER HSER HSER HSER HSER HSER HILE HILE HILE HILE HILE HILE HILE HILE HSER HSER HSER HSER HSER HSER HSER HSER HSER HSER HSER HSER HGLY HGLY HGLY HGLY HGLY HGLY HGLY HGLY HASN HASN HASN HASN HASN HASN HASN HASN H

494949505050505050515151515151515152525252525253535353535354545454555555555656565656565656

12.20612.10910.02112.98013.80713.75413.54515.27215.46013.90014.00315.17215.26912.67912.79612.32511.43316.10017.26416.89915.81518.38417.96217.78617.51517.44116.77418.64519.89818.10218.04116.80516.56216.01714.80614.88013.90416.01416.14415.33015.33617.58918.53019.74717.973

-2.877-1.657-3.962-3.721-3.266-4.316-5.502-3.137-2.078-3.849-4.754-4.273-3.087-4.795-5.869-3.407-6.214-5.176-4.790-4.630-5.022-5.853-7.063-4.068-3.925-5.342-5.539-3.160-3.829-6.314-7.697-8.441-9.593-7.799-8.434-9.146-9.788-9.067-9.673-8.806-7.577-9.632-10.453-10.418-11.194

88.15487.91288.49587.46586.36385.26585.56386.77487.68384.03682.85881.99981.68282.05880.95881.42780.37681.62580.81679.35278.94080.91380.25378.55877.12976.52875.51876.44576.63277.16076.67677.17676.80078.04478.54779.88880.28280.58681.91582.89282.74782.39281.51881.70680.591

19.9224.7416.9421.8821.5721.7823.6021.4521.5820.0517.9617.5319.1617.6623.688.1015.4114.9015.7816.4622.0015.2120.3518.0320.1322.7426.7120.1516.3322.4818.2422.9422.6920.1915.1221.6725.2821.1623.7323.7827.5829.9735.8935.4324.91

HHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH

COCNCCOCONCCOCCCCNCCOCONCCOCONCCONCCONCCOCCON

NCACOCBOG1CG2NCACOCBCGCD1CD2CE1CE2CZOHNCACOCBCGCD1CD2CE1CE2CZOHNCACOCBCGCDNCACOCBCGOD1

THR HTHR HTHR HTHR HTHR HTHR HTHR HTYR HTYR HTYR HTYR HTYR HTYR HTYR HTYR HTYR HTYR HTYR HTYR HTYR HTYR HTYR HTYR HTYR HTYR HTYR HTYR HTYR HTYR HTYR HTYR HPRO HPRO HPRO HPRO HPRO HPRO HPRO HASP HASP HASP HASP HASP HASP HASP H

575757575757575858585858585858585858585959595959595959595959596060606060606061616161616161

14.71113.89614.47515.10412.38912.33211.73214.23214.75413.67413.01316.01417.03316.81718.22417.75919.18018.93219.89813.55312.53312.99613.77911.24610.63310.9369.75510.3899.1949.5288.99612.50112.91211.94110.85412.63411.35411.71412.30711.43110.0459.09512.08313.28714.042

-9.435-8.717-8.890-9.903-9.200-10.589-8.970-7.896-7.889-7.248-6.261-7.016-7.287-6.817-7.945-6.965-8.128-7.613-7.689-7.798-7.347-7.474-8.349-8.248-8.429-9.532-7.477-9.687-7.616-8.736-8.828-6.605-6.760-7.853-8.097-5.379-4.978-5.373-8.462-9.496-8.987-9.743-10.074-10.902-11.166

83.88984.88386.27086.58384.88685.20583.55187.12988.47589.36488.94788.55087.44586.14787.72285.16386.72785.45184.48290.56291.50492.93293.25391.43690.07289.29089.56288.03388.31487.54986.30093.83695.23495.83895.28695.83595.08593.63896.96297.56297.91197.91998.81598.50499.439

19.3816.4719.0121.1417.3925.3016.6920.3517.8217.8213.9816.9121.1820.2524.5317.1632.4233.7341.3917.6319.9718.4424.9920.0122.2014.5322.2014.8220.9225.2127.9717.6818.5223.4321.9819.0817.1515.9622.5623.0023.4426.4422.9827.2427.26

HHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH

NCCOCOCNCCOCCCCCCCONCCOCCCCCCCONCCOCCCNCCOCCO

OD2NCACOCBOGNCACOCBCG1CG2NCACOCBCGCDCENZNCACONCACOCBCGCDNECZNH1NH2NCACOCBCGCD1

ASP HSER HSER HSER HSER HSER HSER HVAL HVAL HVAL HVAL HVAL HVAL HVAL HLYS HLYS HLYS HLYS HLYS HLYS HLYS HLYS HLYS HGLY HGLY HGLY HGLY HARG HARG HARG HARG HARG HARG HARG HARG HARG HARG HARG HPHE HPHE HPHE HPHE HPHE HPHE HPHE H

616262626262626363636363636364646464646464646465656565666666666666666666666667676767676767

13.4829.9128.5987.5516.3458.7519.2427.9676.9687.1476.3016.8196.7017.9788.2638.5537.4316.9859.87010.49311.59512.33612.9316.9675.8764.5443.5934.4713.2223.2052.1442.8722.6732.1563.0132.5901.3253.4294.3774.5275.3566.3445.2914.4963.336

-11.273-7.685-7.107-7.281-7.272-5.600-4.893-7.402-7.562-8.789-9.061-6.253-5.013-6.125-9.483-10.649-11.666-11.943-11.288-12.165-12.977-13.781-15.014-12.177-13.134-12.447-13.076-11.147-10.420-9.377-9.079-9.740-10.671-9.875-8.738-7.468-7.156-6.513-8.805-7.775-8.293-8.982-6.533-5.690-6.190

97.32798.17098.52697.43797.71698.86397.73696.17695.13094.19393.34694.21495.08693.22494.32593.47793.62994.73293.89792.82393.44792.38893.01892.50492.52292.30891.85992.60992.45591.34390.80293.76794.95696.17796.54996.63196.35697.02691.04190.00288.84589.04790.56391.51092.108

28.0027.6424.0022.4222.7122.9922.4423.6126.0427.7628.2725.0519.8622.1234.0137.7336.2140.7240.5049.6967.4684.7892.9434.9933.3933.6540.6929.5423.9927.3626.6224.4920.9326.2826.5823.2820.5023.3328.2528.9427.6128.3532.7635.9032.82

HHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH

ONCCOCONCCOCCCNCCOCCCCNNCCONCCOCCCNCNNNCCOCCC

CD2CE1CE2CZNCACOCBOG1CG2NCACOCBCG1CG2CD1NCACOCBOGNCACOCBCGCDNECZNH1NH2NCACOCBCGOD1OD2N

PHE HPHE HPHE HPHE HTHR HTHR HTHR HTHR HTHR HTHR HTHR HILE HILE HILE HILE HILE HILE HILE HILE HSER HSER HSER HSER HSER HSER HARG HARG HARG HARG HARG HARG HARG HARG HARG HARG HARG HASP HASP HASP HASP HASP HASP HASP HASP HASN H

676767676868686868686869696969696969697070707070707171717171717171717171727272727272727273

4.9342.6204.2363.0814.9625.7265.9645.0094.9404.6605.7357.2277.5467.7568.2458.8529.12710.06010.2997.3697.5427.6517.3806.3265.1488.0808.1977.7187.8559.67910.65412.13212.52213.52914.25313.7927.1906.7887.7097.4985.3334.9145.7593.7418.752

-4.407-5.421-3.644-4.138-7.937-8.301-7.073-6.399-9.382-10.484-9.824-6.779-5.666-6.235-7.357-4.947-3.732-5.907-2.888-5.492-5.962-4.750-3.642-6.838-6.082-4.931-3.810-4.155-5.291-3.350-4.473-4.115-2.868-2.079-2.413-0.972-3.165-3.397-2.502-1.297-2.998-3.198-2.993-3.535-3.105

91.84393.03292.75893.35887.63786.45785.57485.17585.61186.46384.39685.26884.36982.96582.83984.84183.95984.82984.57881.92480.56079.67080.11080.15680.17178.43077.54676.15575.69377.44076.87877.23076.57776.97478.03076.32475.46474.09473.27273.15873.86572.41671.51072.19472.711

27.6737.7434.6741.4828.8229.2428.8129.9531.6328.5117.8624.6625.5827.2231.0926.4318.6728.9322.1224.5920.3520.7622.2018.0119.5321.7422.8025.0528.8822.3217.6313.8426.6320.5113.7317.6124.4124.1825.4525.3127.1730.7833.9838.5826.35

HHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH

CCCCNCCOCOCNCCOCCCCNCCOCONCCOCCCNCNNNCCOCCOON

CACOCBCGOD1ND2NCACOCBNCACOCBCGCDNECZNH1NH2NCACOCBCGOD1ND2NCACOCBCG1CG2CD1NCACOCBCG

ASN HASN HASN HASN HASN HASN HASN HALA HALA HALA HALA HALA HARG HARG HARG HARG HARG HARG HARG HARG HARG HARG HARG HASN HASN HASN HASN HASN HASN HASN HASN HILE HILE HILE HILE HILE HILE HILE HILE HLEU HLEU HLEU HLEU HLEU HLEU H

737373737373737474747474757575757575757575757576767676767676767777777777777777787878787878

9.7209.2359.89510.95811.81211.63212.7598.0767.5956.8526.9226.6606.1895.4086.0975.5654.0713.1111.8250.8531.0292.1570.0457.2717.9957.1146.8838.3479.60610.16210.0456.6245.7836.3476.7504.3143.7523.4552.3326.3816.8745.6454.8667.8518.376

-2.377-1.837-1.011-3.246-3.396-2.669-4.319-2.276-1.739-0.4220.547-2.771-0.3990.7581.6952.7710.276-0.412-0.875-1.612-2.841-3.513-3.4191.3072.1492.3443.4623.5463.5584.6222.4111.2511.2890.293-0.8250.8481.7020.9301.3040.703-0.106-0.3960.5060.7270.043

71.91270.56969.94571.67572.92373.91272.87770.11568.85369.16468.42168.18770.31170.72971.73772.03071.32770.33471.04670.22469.73169.95069.04072.24973.23674.46174.91572.68071.78071.50171.35475.00176.16677.17876.83375.81974.67477.06974.16778.43679.52880.36580.59880.40581.650

29.0431.0228.4031.8832.5342.7433.4132.6532.5733.6931.1629.6232.1232.7529.9628.4835.0440.6161.4568.3369.9460.6170.6827.3922.4524.2627.8522.8830.1945.6927.1320.5521.4326.3527.6725.3131.0224.5018.4127.9124.8924.7625.5024.4918.05

HHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH

CCOCCONNCCOCNCCOCCCNCNNNCCOCCONNCCOCCCCNCCOCC

CD1CD2NCACOCBCGCD1CD2CE1CE2CZOHNCACOCBCGCD1CD2NCACOCBCGCDOE1NE2NCACOCBCGSDCENCACOCBOG

LEU HLEU HTYR HTYR HTYR HTYR HTYR HTYR HTYR HTYR HTYR HTYR HTYR HTYR HLEU HLEU HLEU HLEU HLEU HLEU HLEU HLEU HGLN HGLN HGLN HGLN HGLN HGLN HGLN HGLN HGLN HMET HMET HMET HMET HMET HMET HMET HMET HSER HSER HSER HSER HSER HSER H

78787979797979797979797979798080808080808080818181818181818181828282828282828282A82A82A82A82A82A

9.4499.0685.4844.3304.7205.8273.5252.9523.5651.7913.0481.2771.9081.4233.7793.9472.5921.5994.2454.4685.8364.5522.5501.3181.4092.3791.2240.084-1.266-2.047-1.5430.4280.446-0.719-1.7840.3051.4241.2360.076-0.500-1.553-1.455-0.448-1.309-0.074

-1.0261.102-1.630-1.997-2.514-3.036-3.156-2.791-3.195-2.020-2.848-1.668-2.084-1.711-2.429-3.007-3.669-2.983-1.992-2.735-3.504-1.721-4.993-5.716-6.033-6.674-7.029-7.955-7.341-7.096-7.047-5.573-5.840-6.757-6.580-4.526-3.501-1.930-1.286-7.722-8.656-8.809-8.439-10.011-10.562

81.24182.53280.83381.66283.01483.19380.99479.65278.47979.55677.24778.32377.17375.93583.96485.27285.59685.83586.40987.75487.72188.99285.56385.90587.37687.83285.10485.58085.31686.24884.05388.15389.57989.91189.38690.38090.09791.03690.15390.78991.16192.66493.25390.44590.886

27.0015.7026.1125.6227.7529.8322.6027.0820.9224.6424.7121.7224.8221.4325.4825.7527.5734.2825.2226.5218.2920.6930.1032.0730.5230.7734.2736.0340.1035.5129.7529.3231.6933.4237.2232.5734.8341.3521.3433.8732.6930.3527.6630.9039.97

HHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH

CCNCCOCCCCCCCONCCOCCCCNCCOCCCONNCCOCCSCNCCOCO

NCACOCBOGNCACOCBCGCD1CD2NCAC0CBCGCDNECZNH1NH2NCACOCBOGNCACOCBCGCDOE1OE2NCACOCB

SER HSER HSER HSER HSER HSER HLEU HLEU HLEU HLEU HLEU HLEU HLEU HLEU HARG HARG HARG HARG HARG HARG HARG HARG HARG HARG HARG HSER HSER HSER HSER HSER HSER HGLU HGLU HGLU HGLU HGLU HGLU HGLU HGLU HGLU HASP HASP HASP HASP HASP H

82B82B82B82B82B82B82C82C82C82C82C82C82C82C83838383838383838383838484848484848585858585858585858686868686

-2.456-2.532-2.084-1.256-1.670-1.941-2.646-2.300-2.677-3.731-2.965-2.300-3.142-0.928-1.794-1.967-2.044-1.641-0.753-0.4740.9631.2552.4523.4672.628-2.518-2.634-1.268-1.188-3.221-2.301-0.2181.1741.6932.7282.1531.7150.8441.397-0.3891.0301.4290.8451.0750.906

-9.444-9.614-8.329-8.387-10.769-11.975-7.194-5.892-5.867-6.405-4.745-4.508-3.680-3.764-5.270-5.119-3.624-2.802-5.691-7.134-7.485-8.881-9.433-8.701-10.727-3.268-1.854-1.181-0.048-1.658-1.987-1.906-1.437-1.073-0.431-2.463-3.123-4.321-5.388-4.180-1.524-1.1600.2260.712-2.178

93.27094.73895.46496.38695.24994.54595.05095.68797.15497.56394.92393.55692.58693.85097.95399.40499.69998.859100.11599.749100.03599.73399.885100.32899.618100.887101.209101.096100.617102.606103.617101.491101.453100.07199.984102.036103.296103.003102.632103.10599.00997.65597.27396.14796.624

30.1132.5934.4134.3831.6239.7334.5034.5233.7736.5031.3329.6914.8122.9637.5037.2835.3934.4135.8344.1358.6165.9268.2966.4876.6733.5431.4330.4627.9032.6945.6427.5528.6727.8931.9128.8046.7456.3862.5156.2425.2925.7126.7725.6826.58

HHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH

NCCOCONCCOCCCCNCCOCCCNCNNNCCOCONCCOCCCOONCCOC

CGOD1OD2NCACOCBOG1CG2NCACOCBNCACOCBCGSDCENCACOCBCGCD1CD2CE1CE2CZOHNCACOCBCGCD1CD2CE1CE2

ASP HASP HASP HTHR HTHR HTHR HTHR HTHR HTHR HTHR HALA HALA HALA HALA HALA HMET HMET HMET HMET HMET HMET HMET HMET HTYR HTYR HTYR HTYR HTYR HTYR HTYR HTYR HTYR HTYR HTYR HTYR HTYR HTYR HTYR HTYR HTYR HTYR HTYR HTYR HTYR HTYR H

868686878787878787878888888888898989898989898990909090909090909090909091919191919191919191

1.4180.5862.6270.072-0.5310.6611.447-1.458-2.623-1.8810.7221.8891.8150.9723.1622.7462.8273.7944.8393.5163.6232.0921.5863.4784.3905.0264.3433.6433.3754.1722.3763.9882.1973.0092.8356.3687.0947.7698.3938.2517.7937.8187.3397.4086.901

-3.603-4.562-3.7650.8512.1653.1633.3142.6541.8084.1453.8454.7175.4045.1033.8436.3587.0016.0925.7908.3789.1179.56510.9855.6994.8385.6186.1313.6002.5661.4272.7720.5221.8870.760-0.1145.6696.3845.4004.4417.2168.3388.2089.5259.26010.577

96.87796.76397.17298.17697.84297.69098.59198.95698.99298.70996.56896.35495.05294.18296.36194.86893.57092.83593.39993.67992.35291.50092.55691.59890.83089.71788.83690.21491.28691.39292.25192.42593.28593.36194.38489.72188.65187.68188.12189.22690.13891.50789.58992.33890.398

32.5230.4229.9923.9323.4422.2321.3626.7326.0328.4719.0717.4521.7521.2114.9422.4124.7222.6026.7524.1824.5731.1417.3219.6618.7619.4818.2216.5414.149.3322.6315.9813.3024.2421.0220.3117.1219.9218.1815.4417.089.6615.2916.3415.56

HHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH

COONCCOCOCNCCOCNCCOCCSCNCCOCCCCCCCONCCOCCCCCC

CZOHNCACOCBSGNCACOCBNCACOCBCGCDNECZNH1NH2NCACOCBCGCD1CD2NCACOCBCGOD1OD2NCACON

TYR HTYR HCYS HCYS HCYS HCYS HCYS HCYS HALA HALA HALA HALA HALA HARG HARG HARG HARG HARG HARG HARG HARG HARG HARG HARG HLEU HLEU HLEU HLEU HLEU HLEU HLEU HLEU HASP HASP HASP HASP HASP HASP HASP HASP HGLY HGLY HGLY HGLY HTYR H

919192929292929293939393939494949494949494949494959595959595959596969696969696969797979798

6.9446.5447.6508.3119.7099.7717.6028.42910.80512.10713.06613.03112.73713.89814.87316.03116.60715.32516.05016.47717.73018.30117.70519.52016.39717.46918.73718.91217.11718.30118.89117.83719.59720.81121.90022.91521.33820.50219.31921.00221.66322.57423.12623.06423.737

10.44611.5175.7335.0655.7516.9595.4984.8015.0225.6845.0193.7805.6045.8215.2244.8495.7056.2115.5236.5667.2298.1468.5498.6023.5653.0793.0852.2191.6761.0132.007-0.1924.0784.1873.2203.0655.6176.5196.1847.5132.6271.6011.8212.9350.782

91.75592.54786.39785.27885.27085.43583.98782.56985.09585.08584.06883.89886.46283.40282.48083.37484.05881.41780.23879.24279.58078.81877.66479.14283.35084.21783.37582.51584.70085.43086.39086.13683.58082.75883.24282.56982.72381.75581.57881.22484.40284.92286.31086.84186.887

21.428.8121.5522.1020.9420.4318.8132.6018.5215.7915.4020.1616.7815.8917.4317.1016.1113.4515.8613.7917.2920.3513.0415.8219.0917.6419.4620.8116.9719.8126.5617.5718.6418.9718.9414.6320.0919.5826.6911.7215.6616.1716.4814.7512.61

HHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH

CONCCOCSNCCOCNCCOCCCNCNNNCCOCCCCNCCOCCOONCCON

CACOCBCGCD1CD2CE1CE2CZOHNCACOCBCGCD1CD2CE1CE2CZOHNCACOCBCGCD1CD2CE1CE2CZNCACONCACOCBCGCD1

TYR HTYR HTYR HTYR HTYR HTYR HTYR HTYR HTYR HTYR HTYR HTYR HTYR HTYR HTYR HTYR HTYR HTYR HTYR HTYR HTYR HTYR HTYR HPHE HPHE HPHE HPHE HPHE HPHE HPHE HPHE HPHE HPHE HPHE HGLY HGLY HGLY HGLY HPHE HPHE HPHE HPHE HPHE HPHE HPHE H

9898989898989898989898999999999999999999999999100100100100100100100100100100100100A100A100A100A100B100B100B100B100B100B100B

24.25925.37425.59824.70925.76227.12325.38428.08926.33027.65128.55326.02527.03826.47627.21328.12729.11229.94029.20630.87230.14530.95131.81325.18524.56323.28322.93024.26825.55025.91826.35327.06827.51527.86222.60421.38120.10820.10519.01317.72217.79717.53716.57916.43516.614

0.9582.0292.639-0.385-1.194-1.116-2.089-1.955-2.917-2.853-3.7232.3083.3824.7825.7553.1022.0302.2650.7851.295-0.2220.069-0.9174.8556.0956.5447.7255.9775.8354.5976.9214.4696.7975.5635.6155.9866.0475.7146.5166.6398.0419.0286.5505.1815.011

88.22688.27189.29988.87088.10488.45087.12487.82286.48986.83886.27787.15487.16086.87486.93086.07386.52287.61385.85088.06386.27587.38687.79586.51886.06386.78986.70584.52983.67783.13683.42682.35882.63982.11087.46688.19787.36486.19287.98087.26686.66587.34788.32188.95290.323

13.4814.6615.4215.1112.1918.1712.4818.608.789.4613.7110.2511.4213.3811.939.5811.2416.6315.7217.9620.4216.7414.9314.0512.9415.0016.9013.5312.8412.6515.2412.1414.0012.3213.8512.5613.5616.7214.2216.0919.5118.5815.6717.5812.85

HHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH

CCOCCCCCCCONCCOCCCCCCCONCCOCCCCCCCNCCONCCOCCC

CD2CE1CE2CZNCACOCBNCACOCBCGCD1CD2CE1CE2CZOHNCACOCBCGCD1CD2NE1CE2CE3CZ2CZ3CH2NCACONCACOCBN

PHE HPHE HPHE HPHE HALA HALA HALA HALA HALA HTYR HTYR HTYR HTYR HTYR HTYR HTYR HTYR HTYR HTYR HTYR HTYR HTRP HTRP HTRP HTRP HTRP HTRP HTRP HTRP HTRP HTRP HTRP HTRP HTRP HTRP HGLY HGLY HGLY HGLY HALA HALA HALA HALA HALA HGLY H

100B100B100B100B101101101101101102102102102102102102102102102102102103103103103103103103103103103103103103103104104104104105105105105105106

16.07416.44415.90316.08318.09818.37517.17517.29519.29516.04314.81613.64513.57214.59315.58516.75715.40217.74716.37217.53718.47512.72811.56410.29910.30611.59512.76014.09012.68514.85214.02411.62314.32811.92513.2819.2167.9477.2587.8865.9795.2844.6494.2184.1854.600

4.0693.7642.7992.6568.1239.41810.27811.4899.2649.64710.3619.6938.47110.29611.14010.59112.51311.42113.34312.78213.60210.51210.00310.56511.67610.4599.94710.1989.1649.6138.9688.6078.2517.8887.7099.79210.30311.16911.53511.50812.34411.52412.07813.22010.191

88.17790.92388.79290.15585.36484.77884.39184.34883.59484.13083.74584.42084.47282.23581.52381.02881.45680.47180.91180.41979.83284.92185.63285.00984.47287.11087.94787.72189.13588.70689.59089.87890.71091.01591.42685.07184.54285.60486.60685.40086.35687.46888.46585.60687.314

13.1713.9112.449.2620.2416.3817.0321.3113.6518.1417.0417.3514.9217.9520.2520.0120.0016.2415.5217.9232.9917.0317.0015.3118.7218.5822.4210.3513.2424.9911.3813.129.1413.8213.9716.9820.0322.0022.6024.5223.3921.5224.7524.9421.97

HHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH

CCCCNCCOCNCCOCCCCCCCONCCOCCCCNCCCCCNCCONCCOCN

CACONCACOCBOG1CG2NCACOCBCGCD1CD2NCACOCBCG1CG2NCACOCBNCACOCBCG1CG2NCACOCBOGNCA

GLY HGLY HGLY HTHR HTHR HTHR HTHR HTHR HTHR HTHR HLEU HLEU HLEU HLEU HLEU HLEU HLEU HLEU HVAL HVAL HVAL HVAL HVAL HVAL HVAL HALA HALA HALA HALA HALA HVAL HVAL HVAL HVAL HVAL HVAL HVAL HSER HSER HSER HSER HSER HSER HALA HALA H

106106106107107107107107107107108108108108108108108108109109109109109109109110110110110110111111111111111111111112112112112112112113113

4.1282.6101.8722.1600.7270.3060.8620.421-0.9951.030-0.687-1.066-1.862-2.801-1.900-1.075-1.415-1.299-1.423-2.177-2.662-1.892-1.276-1.965-0.991-3.995-4.549-5.218-6.145-5.561-4.788-5.337-6.192-5.686-4.207-4.820-3.279-7.506-8.423-9.780-10.182-8.603-9.559-10.487-11.824

9.1969.0259.9107.8137.5426.9245.9396.5746.4325.2027.5647.1395.8315.6308.2529.15010.6318.8354.9033.6693.5313.5092.4871.1802.4733.4733.3441.9841.6044.4711.231-0.0960.0680.211-1.118-2.488-1.2460.0470.257-0.337-0.4821.7612.071-0.646-1.173

88.26688.18387.77288.55488.56689.90190.36787.42387.29787.72890.54191.88691.88791.12992.51993.44293.26694.92192.76092.94694.39095.34092.59392.98291.10494.54195.88396.09695.39396.09297.09097.33898.56299.66097.63097.98596.36898.34599.43199.11297.94699.645100.646100.169100.013

23.6623.0324.0922.7121.9121.1118.2027.9433.9317.6124.5825.5321.6523.6430.9020.0020.0020.0022.2822.7625.9722.4222.6112.4215.9727.5034.1630.5528.3234.6729.8431.8031.9431.6534.0631.4127.1633.0533.7036.7937.1732.7226.8438.9841.14

HHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH

CCONCCOCOCNCCOCCCCNCCOCCCNCCOCNCCOCCCNCCOCONC

COCBNCACOCBNCACOCBNCACOCBOG1CG2NCACOCBOG1CG2NCACOCBCGCDNCACOCBCGCDNCACO

ALA HALA HALA HALA HALA HALA HALA HALA HALA HALA HALA HALA HALA HTHR HTHR HTHR HTHR HTHR HTHR HTHR HTHR HTHR HTHR HTHR HTHR HTHR HTHR HPRO HPRO HPRO HPRO HPRO HPRO HPRO HPRO HPRO HPRO HPRO HPRO HPRO HPRO HSER HSER HSER HSER H

113113113114114114114114115115115115115116116116116116116116117117117117117117117118118118118118118118119119119119119119119120120120120

-12.805-13.983-12.160-12.325-13.182-13.707-13.135-12.458-14.798-15.460-15.153-15.027-16.987-15.090-14.834-15.916-17.121-14.893-13.832-14.752-15.514-16.507-16.052-14.886-16.597-16.771-17.789-16.949-16.564-16.494-17.221-17.684-18.908-18.372-15.633-15.571-16.672-17.268-14.241-14.176-14.588-16.914-17.822-16.869-16.006

0.001-0.202-2.0551.2162.4032.6732.2183.6113.4313.7255.0776.0683.5845.1016.3227.3176.9856.0445.1387.3148.5289.56910.81011.1819.8678.64010.76511.45712.66813.86113.92712.82112.36911.13214.83715.98316.98517.02416.62016.37914.91717.81818.94120.13520.275

99.95999.665101.202100.256100.24098.84797.839100.76398.79697.53796.94697.65297.70795.62294.88295.22495.19893.38593.04692.58295.59495.90195.19395.30997.38598.09897.65294.42693.70294.65595.62392.66493.47294.20694.36295.27395.04393.97294.92493.41393.32796.05095.88895.80596.642

38.8742.0143.5635.0432.2234.2736.9027.2534.7437.8035.6234.3039.5732.1532.3432.9237.0732.9641.9333.4836.2234.7632.8232.9433.7739.0134.0133.7035.9335.7240.1333.6934.1534.5735.0333.2631.2533.2633.7631.6335.3231.1628.9526.0828.02

HHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH

COCNCCOCNCCOCNCCOCOCNCCOCOCNCCOCCCNCCOCCCNCCO

CBOGNCACOCBCG1CG2NCACOCBCGCD1CD2CE1CE2CZOHNCACOCBCGCDNCACOCBCGCD1CD2NCACOCBNCACO

SER HSER HVAL HVAL HVAL HVAL HVAL HVAL HVAL HTYR HTYR HTYR HTYR HTYR HTYR HTYR HTYR HTYR HTYR HTYR HTYR HPRO HPRO HPRO HPRO HPRO HPRO HPRO HLEU HLEU HLEU HLEU HLEU HLEU HLEU HLEU HALA HALA HALA HALA HALA HPRO HPRO HPRO HPRO H

120120121121121121121121121122122122122122122122122122122122122123123123123123123123124124124124124124124124125125125125125126126126126

-18.763-19.749-17.007-16.132-16.877-17.939-15.651-14.748-14.936-16.349-17.044-16.203-15.032-17.433-18.344-19.571-18.003-20.425-18.861-20.059-20.912-16.812-16.066-15.828-16.675-16.971-18.354-18.245-14.671-14.326-14.143-13.148-13.026-13.138-11.734-14.254-15.139-15.087-15.210-15.840-16.260-14.621-14.664-16.007-16.816

19.08118.04920.96922.12023.37423.65422.19523.38120.85924.12925.34126.56126.54825.22124.06923.95123.10322.89822.04021.95020.89527.66828.90629.62929.60129.72329.36727.83930.27931.04332.50532.88330.50329.02128.60628.78133.32834.75535.53735.05735.10236.74437.59638.20538.560

97.07897.00994.77694.60395.00694.48193.12492.92792.73895.96296.42696.27996.57797.90498.19997.54699.13597.82599.42698.76799.02895.85595.68597.01197.89994.76795.26595.51397.12798.32597.92297.27098.95999.35299.873100.41698.27297.95699.281100.19897.03099.375100.585100.986100.135

29.7435.8522.5520.7122.2727.6517.0015.8316.7325.4124.8824.6824.3824.1829.2325.0625.3521.1021.8026.1034.5926.0722.9225.1229.5926.9722.9726.4926.0724.4628.4428.5924.1325.0318.8212.7833.6534.9037.3935.6333.4844.3448.1753.4353.07

HHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH

CONCCOCCCNCCOCCCCCCCONCCOCCCNCCOCCCCNCCOCNCCO

CBCGCDNCACOOXTNCACOCBCGOD1ND2NCACOCBOGNCACOCBCGSDCENCACOCBCG1CG2NCACOCBOG1CG2N

PRO HPRO HPRO HGLY HGLY HGLY HGLY HGLY HASN HASN HASN HASN HASN HASN HASN HASN HSER HSER HSER HSER HSER HSER HMET HMET HMET HMET HMET HMET HMET HMET HVAL HVAL HVAL HVAL HVAL HVAL HVAL HTHR HTHR HTHR HTHR HTHR HTHR HTHR HLEU H

126126126127127127127127133133133133133133133133134134134134134134135135135135135135135135136136136136136136136137137137137137137137138

-13.650-13.593-13.652-16.210-17.427-17.313-16.226-18.294-7.670-6.184-5.627-6.373-5.588-6.609-6.246-7.882-4.312-3.669-4.089-4.406-2.146-1.411-4.095-4.446-5.703-6.094-3.300-1.919-1.916-1.602-6.345-7.479-7.179-6.608-8.853-8.827-9.967-7.508-7.299-8.644-9.628-6.612-5.301-6.425-8.696

38.69738.73337.27738.35238.96440.47240.95041.19746.71746.77446.46946.23045.80244.88944.02645.06446.48646.25144.94144.91446.29445.90543.85242.51241.91242.31541.53641.97042.01240.23740.95640.27538.76038.28940.54940.11639.75938.02836.57335.85536.18336.14836.74134.61034.910

100.28198.73598.392102.299102.811102.691102.314102.96299.32799.36898.00597.068100.384101.017101.820100.68097.89196.61195.95294.76096.81995.66996.72596.18696.82397.90196.46195.96694.16793.76196.15896.78996.71495.72796.11294.63596.85497.77697.75697.59298.26999.04499.08199.11596.665

48.4746.7747.7758.9062.4465.5667.6169.0761.2458.8354.1254.2061.2068.3978.2780.3446.5843.6440.8638.9748.4251.6940.3434.5732.4430.1535.2537.8548.8945.3229.3029.6127.6221.5328.9630.3019.1826.5827.6029.3028.4026.8129.6127.5828.45

HHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH

CCCNCCOONCCOCCONNCCOCONCCOCCSCNCCOCCCNCCOCOCN

CACOCBCGCD1CD2NCACONCACOCBSGNCACOCBCGCD1CD2NCACOCBCG1CG2NCACOCBCGCDCENZNCACO

LEU HLEU HLEU HLEU HLEU HLEU HLEU HGLY HGLY HGLY HGLY HCYS HCYS HCYS HCYS HCYS HCYS HLEU HLEU HLEU HLEU HLEU HLEU HLEU HLEU HVAL HVAL HVAL HVAL HVAL HVAL HVAL HLYS HLYS HLYS HLYS HLYS HLYS HLYS HLYS HLYS HGLY HGLY HGLY HGLY H

138138138138138138138139139139139140140140140140140141141141141141141141141142142142142142142142143143143143143143143143143144144144144

-9.875-9.475-8.305-10.312-10.498-10.849-11.628-10.444-10.060-11.156-12.255-10.847-11.784-11.571-10.418-11.557-12.544-12.676-12.622-13.066-14.169-13.598-13.729-12.371-14.797-12.205-12.486-12.671-11.708-11.293-11.611-11.007-13.938-14.254-14.891-15.787-15.156-15.507-16.282-16.877-15.810-14.419-14.944-14.856-15.897

34.11732.65832.32634.26535.73535.82636.35031.77630.37029.40429.82328.11727.04025.94725.60726.44727.32125.39724.28923.03023.00424.56023.49023.26423.93522.00720.74419.72119.14020.37019.08421.53419.46318.65017.30317.12419.49718.91719.99119.39618.79016.38115.03814.12813.622

96.39096.58096.79594.93594.48292.95095.31296.47596.58096.16995.79696.26295.97297.00197.32194.56293.29797.52198.51297.77797.19399.692100.794101.553101.79097.77197.07598.18798.69396.19495.36595.23398.51299.66499.48698.656100.574101.941102.758104.058104.927100.312100.37999.18098.714

23.4023.5725.0123.5530.5619.6935.2019.2621.1222.3219.4319.1123.5223.2222.9125.7344.8021.5320.4818.8922.7117.1725.3825.2221.0315.0315.1318.3219.2216.1216.0516.5219.2223.5023.9528.6821.9825.0628.3728.9044.6824.1926.6227.6530.78

HHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH

CCOCCCCNCCONCCOCSNCCOCCCCNCCOCCCNCCOCCCCNNCCO

NCACOCBCGCD1CD2CE1CE2CZOHNCACOCBCGCD1CD2CE1CE2CZNCACOCBCGCDNCACOCBCGCDOE1OE2NCACOCBCG

TYR HTYR HTYR HTYR HTYR HTYR HTYR HTYR HTYR HTYR HTYR HTYR HPHE HPHE HPHE HPHE HPHE HPHE HPHE HPHE HPHE HPHE HPHE HPRO HPRO HPRO HPRO HPRO HPRO HPRO HGLU HGLU HGLU HGLU HGLU HGLU HGLU HGLU HGLU HPRO HPRO HPRO HPRO HPRO HPRO H

145145145145145145145145145145145145146146146146146146146146146146146147147147147147147147148148148148148148148148148149149149149149149

-13.635-13.398-12.535-11.889-12.743-11.357-10.204-11.196-8.897-9.926-8.793-7.553-12.555-11.737-11.753-12.805-12.306-11.379-10.421-11.440-9.550-10.541-9.600-10.591-9.315-8.572-9.112-8.582-8.879-10.416-7.335-6.490-6.174-6.178-5.206-5.450-4.209-3.378-4.080-5.806-5.671-6.724-7.597-4.314-4.455

13.91413.01611.81411.80213.75914.30613.58615.55314.11216.06115.35615.86410.7809.5868.8128.6978.6907.5567.7406.3346.7555.3235.5308.3218.4779.70410.4437.2147.1727.4679.90110.96310.4319.21911.08411.62812.17611.33213.44111.31312.76013.56913.02613.03412.232

98.69097.55097.92098.97096.37896.68396.33897.28396.57597.53997.18497.46197.05697.26495.96095.32898.35998.76799.75798.121100.09198.46499.44395.52796.20995.66994.86695.80694.37794.33296.12895.56294.16293.95196.34497.70198.29498.73598.29493.21693.42692.70792.03592.80991.462

26.7627.1729.5325.9824.0828.0630.3722.5025.1720.8228.2017.9331.0531.4332.0836.1629.0227.0022.3627.6821.9527.2922.3627.5726.6426.2125.8923.3625.9426.7426.2829.1428.2632.8127.6028.1546.5856.9337.3828.6426.3924.5523.8828.3520.74

HHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH

NCCOCCCCCCCONCCOCCCCCCCNCCOCCCNCCOCCCOONCCOCC

CDNCACOCBCG1CG2NCACOCBOG1CG2NCACOCBCG1CG2NCACOCBOG1CG2NCACOCBCGCD1CD2NE1CE2CE3CZ2CZ3CH2NCA

PRO HVAL HVAL HVAL HVAL HVAL HVAL HVAL HTHR HTHR HTHR HTHR HTHR HTHR HTHR HVAL HVAL HVAL HVAL HVAL HVAL HVAL HTHR HTHR HTHR HTHR HTHR HTHR HTHR HTRP HTRP HTRP HTRP HTRP HTRP HTRP HTRP HTRP HTRP HTRP HTRP HTRP HTRP HASN HASN H

149150150150150150150150151151151151151151151152152152152152152152153153153153153153153154154154154154154154154154154154154154154155155

-5.192-6.627-7.448-6.429-5.306-8.414-9.577-7.665-6.811-5.939-6.700-7.915-5.597-6.802-4.824-5.980-6.578-5.755-4.544-6.625-7.340-7.372-6.385-5.667-6.627-7.765-5.395-6.632-4.566-6.150-6.961-6.981-5.952-6.389-6.641-5.828-7.800-6.430-7.638-8.964-8.608-9.929-9.737-8.144-8.219

10.91314.89015.80916.76916.89716.65115.75117.36917.44118.43619.74219.76518.15318.05216.85920.80822.12723.16123.22822.62324.01421.60923.91524.99626.21126.06124.65924.41223.43527.39328.60029.19529.28829.59829.17528.40629.49928.24128.90030.23129.02430.35229.74829.56030.047

91.93292.86892.11391.53292.03592.94493.47894.09690.47189.93590.04989.86988.48187.69488.40290.36490.43689.63089.79291.89791.93092.78488.73688.04888.13288.56586.55185.88986.45087.75287.75486.34285.68988.74890.18590.99890.95792.24492.23990.69393.25491.70592.97285.86784.479

28.5623.2919.2124.2326.4218.0917.9510.7124.6330.4328.7826.2931.7043.9536.2726.6225.2323.0127.0425.9622.7025.0420.6023.6724.1125.7124.2825.9119.3128.4332.0330.2029.0133.7133.7925.7332.1221.1827.4025.2429.4430.0424.7730.3037.67

HHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH

CNCCOCCCNCCOCOCNCCOCCCNCCOCOCNCCOCCCCNCCCCCNC

COCBCGOD1ND2NCACOCBOGNCACONCACOCBOGNCACOCBCGCD1CD2NCACOCBOGNCACOCBOGNCAC

ASN HASN HASN HASN HASN HASN HSER HSER HSER HSER HSER HSER HGLY HGLY HGLY HGLY HSER HSER HSER HSER HSER HSER HLEU HLEU HLEU HLEU HLEU HLEU HLEU HLEU HSER HSER HSER HSER HSER HSER HSER HSER HSER HSER HSER HSER HGLY HGLY HGLY H

155155155155155155156156156156156156157157157157158158158158158158159159159159159159159159160160160160160160161161161161161161162162162

-7.488-6.758-7.740-8.733-9.845-8.376-7.712-7.123-5.612-4.972-7.672-9.060-5.040-3.601-3.067-1.869-3.940-3.528-3.142-2.390-4.652-4.650-3.668-3.396-2.548-3.049-4.734-4.879-3.662-6.162-1.268-0.3270.5090.7070.6071.0041.0371.8630.926-0.2372.7431.9441.4100.551-0.598

29.18129.68631.49632.41531.98033.68327.87626.91626.99726.65727.14126.86727.43527.54728.92929.14029.87831.25532.01932.98132.04131.78231.58432.23031.22530.19732.46233.24234.08134.08231.52230.62031.10530.37830.08928.78332.30832.78133.20933.53833.96635.11033.15933.55032.579

83.44382.59384.41385.03085.38285.17083.52882.61282.59281.59281.20081.13583.70683.80383.53483.69883.15782.85284.08784.02682.15380.78185.21786.49487.24487.73087.18688.47388.75888.32087.32987.95889.14490.11586.87787.20889.08090.18591.32491.08489.71889.46792.55693.66693.971

37.8537.1234.7535.4944.0845.8237.3436.5836.1238.5137.4037.9130.7726.6829.6227.3231.5633.9636.3441.3232.9239.5339.2538.7636.8939.6441.0045.9244.0746.7835.3637.8434.8535.0639.5754.8633.7135.4633.8535.1733.2238.8430.8433.8234.76

HHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH

COCCONNCCOCONCCONCCOCONCCOCCCCNCCOCONCCOCONCC

ONCACOCBCG1CG2NCACOCBCGND1CD2CE1NE2NCACOCBOG1CG2NCACOCBCGCD1CD2CE1CE2CZNCACOCBCGCDNCA

GLY HVAL HVAL HVAL HVAL HVAL HVAL HVAL HHIS HHIS HHIS HHIS HHIS HHIS HHIS HHIS HHIS HHIS HTHR HTHR HTHR HTHR HTHR HTHR HTHR HPHE HPHE HPHE HPHE HPHE HPHE HPHE HPHE HPHE HPHE HPHE HPRO HPRO HPRO HPRO HPRO HPRO HPRO HALA HALA H

162163163163163163163163164164164164164164164164164164165165165165165165165166166166166166166166166166166166167167167167167167167168168

-1.590-0.499-1.520-0.9200.275-1.803-2.545-2.650-1.746-1.297-2.280-3.363-1.242-0.0751.236-0.0202.0441.307-1.932-2.866-2.371-1.277-2.913-3.554-3.750-3.181-2.747-2.826-3.701-3.553-3.345-3.999-2.386-3.663-2.056-2.693-1.914-1.971-3.327-3.865-0.8540.133-0.790-3.846-5.123

32.93131.35730.35629.48329.22329.43528.16830.20829.02928.10926.96027.11728.73129.63329.20530.95130.23631.30025.80824.68023.86923.33023.85624.64822.57523.75223.04221.50020.93623.54725.02725.99725.41527.35426.75627.71820.80519.32518.85319.41918.89820.03021.27917.77917.227

94.63493.46893.74894.82194.80592.50892.95891.43195.77296.78096.85397.41598.16298.36098.22798.65398.42698.68496.28796.43497.62297.58995.11394.10795.29998.67799.85799.76999.109101.085101.375100.633102.291100.804102.470101.721100.440100.401100.950101.913101.368101.292101.282100.377100.818

38.6533.1827.5227.5327.1328.9026.6027.6625.6422.4420.6920.7819.6229.0526.9231.2815.9626.4419.7319.4616.2620.0518.4419.7813.6815.6415.4615.5518.7312.3211.2411.467.747.4617.1018.0214.9115.3217.2517.8011.9619.5317.9921.7021.19

HHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH

ONCCOCCCNCCOCCNCCNNCCOCOCNCCOCCCCCCCNCCOCCCNC

COCBNCACOCBCG1CG2NCACOCBCGCD1CD2NCACOCBNCACOCBOGNCACOCBNCACOCBCGCD1CD2NCAC

ALA HALA HALA HVAL HVAL HVAL HVAL HVAL HVAL HVAL HLEU HLEU HLEU HLEU HLEU HLEU HLEU HLEU HALA HALA HALA HALA HALA HSER HSER HSER HSER HSER HSER HALA HALA HALA HALA HALA HLEU HLEU HLEU HLEU HLEU HLEU HLEU HLEU HTYR HTYR HTYR H

168168168169169169169169169169170170170170170170170170171171171171171172172172172172172173173173173173174174174174174174174174175175175

-4.982-3.910-5.584-6.066-6.062-7.177-8.269-6.329-6.454-5.155-6.868-7.797-8.536-7.909-7.042-7.913-8.703-7.010-9.866-10.744-11.937-12.513-11.254-12.268-13.386-13.438-14.468-14.693-14.605-12.316-12.221-12.433-12.644-13.182-12.418-12.548-11.479-11.151-13.921-15.150-16.442-15.089-10.999-9.983-10.651

16.62516.16116.14216.64616.06615.02515.27217.08316.37218.08813.87012.75812.71912.71111.43810.18110.0238.98812.67612.57011.63111.68513.95510.7499.8369.2839.37910.55711.2948.7178.1369.0848.6256.94610.39811.29912.39112.81712.00011.06011.87810.32612.82813.87715.217

102.200102.57499.847102.963104.288104.330103.881105.345106.715105.368104.896104.952106.248107.305104.807104.914103.629105.199106.155107.322106.998105.922107.735107.939107.783106.381105.680108.097109.313105.955104.638103.459102.354104.518103.674102.523102.637103.719102.465102.332102.384101.005101.487101.391101.148

24.1023.8321.7423.3325.3728.1327.2528.3729.4224.4832.3432.9735.0435.4332.8835.4122.5627.8037.8642.5545.5945.2243.3748.6850.2250.0454.8851.9458.5546.4544.3540.4941.8646.9836.4132.1530.1530.8532.7825.2612.3620.9827.6427.1125.89

HHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH

COCNCCOCCCNCCOCCCCNCCOCNCCOCONCCOCNCCOCCCCNCC

OCBCGCD1CD2CE1CE2CZOHNCACOCBOG1CG2NCACOCBCGCD1CD2NCACOCBOGNCACOCBOGNCACOCBOGNCAC

TYR HTYR HTYR HTYR HTYR HTYR HTYR HTYR HTYR HTHR HTHR HTHR HTHR HTHR HTHR HTHR HLEU HLEU HLEU HLEU HLEU HLEU HLEU HLEU HSER HSER HSER HSER HSER HSER HSER HSER HSER HSER HSER HSER HSER HSER HSER HSER HSER HSER HVAL HVAL HVAL H

175175175175175175175175175176176176176176176176177177177177177177177177178178178178178178179179179179179179180180180180180180181181181

-11.699-9.092-8.129-6.952-8.411-6.065-7.540-6.376-5.552-10.025-10.483-9.248-8.234-11.276-12.527-11.531-9.312-8.179-8.730-9.895-7.157-7.270-7.486-5.957-7.866-8.247-7.121-5.998-8.445-7.328-7.410-6.422-6.798-7.983-6.515-5.567-5.800-6.028-5.301-4.302-5.458-4.048-5.809-5.165-5.303

15.27913.60112.49112.69811.20911.65410.16110.3869.32516.28217.63018.51018.37318.21817.51919.67719.37820.26621.62121.75019.75719.74521.14719.17722.63123.97724.56324.06724.86624.87425.67826.34727.83528.19025.82926.51928.67730.11130.72230.16330.69430.66131.86232.57234.070

100.499100.185100.404101.11999.935101.376100.172100.895101.168101.641101.373101.109101.772102.575102.692102.381100.11299.95499.55999.20598.90897.37496.82696.74099.64399.24798.40498.432100.475101.31797.72796.87796.92196.80695.40594.58297.14197.19096.00395.51898.47698.48895.54494.45094.779

22.5928.7133.1936.5030.2136.8742.6746.8852.4524.2424.9922.3522.3223.2231.7410.3022.6925.0624.3022.6121.5726.7030.9115.9422.7517.8421.1424.2213.3513.3117.8021.5518.8216.7515.4121.6417.8821.7024.1626.1514.1822.6324.7628.3231.11

HHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH

OCCCCCCCONCCOCOCNCCOCCCCNCCOCONCCOCONCCOCONCC

OCBCG1CG2NCACOCBOG1CG2NCACOCBCG1CG2NCACOCBCGCDNCACOCBOGNCACOCBOGNCACOCBCGCDN

VAL HVAL HVAL HVAL HTHR HTHR HTHR HTHR HTHR HTHR HTHR HVAL HVAL HVAL HVAL HVAL HVAL HVAL HPRO HPRO HPRO HPRO HPRO HPRO HPRO HSER HSER HSER HSER HSER HSER HSER HSER HSER HSER HSER HSER HPRO HPRO HPRO HPRO HPRO HPRO HPRO HARG H

181181181181182182182182182182182183183183183183183183184184184184184184184185185185185185185186186186186186186187187187187187187187188

-6.373-5.777-7.239-4.989-4.211-4.218-4.005-3.093-3.128-3.283-3.195-4.848-4.783-5.049-5.559-5.858-5.723-7.238-4.671-4.892-6.376-7.275-4.385-3.269-3.966-6.639-8.029-8.816-9.997-8.066-7.310-8.143-8.744-9.408-10.570-7.685-6.732-8.660-9.086-10.349-11.042-7.872-6.774-7.184-10.652

34.53432.19832.58532.89034.81036.23437.02036.70736.55235.72038.02338.02538.81640.27840.55938.32236.80238.61341.22542.66342.98642.51643.32342.37341.02043.80144.15944.60244.27745.30845.02445.35345.89644.84344.98946.64647.22343.79342.66741.92141.38241.76542.75843.82641.865

95.25293.10793.05591.96594.59094.90993.62792.85095.87597.03396.27793.40592.17592.53593.61691.14990.92191.65091.64791.90392.16091.44090.62590.16990.36893.17093.49692.25492.09894.51295.65791.38590.15889.27088.89689.35790.22188.88988.05688.48687.64588.08987.95488.95389.779

27.7625.9624.2328.5932.7034.0336.5037.9831.3740.5032.6539.2437.3340.5943.7535.3623.9830.5144.2943.6945.0545.2243.9042.3244.9845.1550.3251.8253.1952.2355.3055.7058.7061.2961.1959.1158.6062.6561.5761.3862.1260.0364.0465.5158.01

HHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH

OCCCNCCOCOCNCCOCCCNCCOCCCNCCOCONCCOCONCCOCCCN

CACOCBCGCDNECZNH1NH2NCACOCBCGCDNCACOCBOGNCACOCBCGCDOE1OE2NCACOCBOG1CG2NCACOCBCG1

ARG HARG HARG HARG HARG HARG HARG HARG HARG HARG HPRO HPRO HPRO HPRO HPRO HPRO HPRO HSER HSER HSER HSER HSER HSER HGLU HGLU HGLU HGLU HGLU HGLU HGLU HGLU HGLU HTHR HTHR HTHR HTHR HTHR HTHR HTHR HVAL HVAL HVAL HVAL HVAL HVAL H

188188188188188188188188188188189189189189189189189190190190190190190191191191191191191191191191192192192192192192192193193193193193193

-11.843-12.869-12.512-11.440-11.888-13.080-13.208-14.092-14.932-14.137-14.164-14.695-14.844-15.582-16.045-16.485-15.246-14.158-14.255-13.721-14.329-13.471-12.074-12.573-11.954-12.266-12.058-10.448-10.003-8.493-7.771-8.020-12.749-13.137-12.015-10.920-13.983-13.208-15.162-12.309-11.346-12.108-13.128-10.821-9.893

41.13741.98642.89439.92038.57438.05738.80638.53537.52639.27041.71440.68441.14440.53240.37841.71242.28942.22042.72441.67041.39544.04143.87041.10140.05338.76538.69140.25941.39441.57140.54842.72837.75336.49835.60835.58135.68135.33536.50834.88433.95932.66332.64134.47733.432

90.19290.93291.68791.04190.46691.21292.45193.39793.25094.49290.70589.81588.36187.59990.43290.88391.52287.98586.61585.64684.60486.45386.60785.99285.19685.95287.15585.11284.20784.23484.30984.17985.24385.87786.40885.86184.92083.77084.48187.49488.09688.28588.93289.46990.119

53.4653.1755.7551.6547.1424.9525.4430.9329.8729.1349.0350.1254.8054.4449.0945.1245.6758.6559.7060.4862.9260.5560.0857.1355.5553.4354.3857.0957.6873.3473.7381.1750.9448.1844.6442.8347.3952.7548.6838.7635.6530.6630.7136.3040.07

HHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH

CCOCCCNCNNNCCOCCCNCCOCONCCOCCCOONCCOCOCNCCOCC

CG2NCACOCBOG1CG2NCACOCBSGNCACOCBCGOD1ND2NCACOCBCG1CG2NCACOCBNCACOCBCGND1CD2CE1NE2N

VAL HTHR HTHR HTHR HTHR HTHR HTHR HTHR HCYS HCYS HCYS HCYS HCYS HCYS HASN HASN HASN HASN HASN HASN HASN HASN HVAL HVAL HVAL HVAL HVAL HVAL HVAL HALA HALA HALA HALA HALA HHIS HHIS HHIS HHIS HHIS HHIS HHIS HHIS HHIS HHIS HPRO H

193194194194194194194194195195195195195195196196196196196196196196197197197197197197197198198198198198199199199199199199199199199199200

-10.021-11.609-12.289-11.313-10.205-12.922-13.895-13.599-11.689-10.779-11.260-12.448-10.746-12.275-10.331-10.679-10.263-9.078-9.950-9.856-8.794-10.980-11.243-10.980-11.344-12.446-11.811-11.512-11.467-10.431-10.724-10.374-9.376-9.937-11.234-11.037-11.232-12.321-12.073-11.912-12.952-10.859-12.542-11.280-10.174

35.75031.58430.29829.19929.16429.96630.96228.61428.31327.22225.97925.68426.92426.22025.27324.07722.87122.66824.08925.47326.09025.97222.04720.86919.58219.45820.93719.73122.23718.62317.32816.23716.31417.12515.22414.07812.84712.25414.03412.86712.00412.45611.12811.38412.430

89.25387.69887.76688.15087.61986.36586.04986.34589.08189.42488.67088.59390.93491.58688.07787.32188.11488.36585.97485.38885.38584.88788.47589.29088.58788.04190.61191.49091.35588.60788.00488.99989.73286.66689.03589.90289.03288.99290.99891.89592.18492.63293.08693.37988.346

36.6327.2531.8430.5635.1034.3038.3625.6727.9728.8428.1331.7627.3335.6427.6929.0126.9123.6631.5129.5025.6434.5524.9823.3725.8429.9224.0323.6716.8428.0729.4629.7428.5831.8332.5333.8637.4241.7632.1231.4937.9425.8836.2727.4138.60

HHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH

CNCCOCOCNCCOCSNCCOCCONNCCOCCCNCCOCNCCOCCNCCNN

CACOCBCGCDNCACOCBNCACOCBOGNCACOCBOGNCACOCBOG1CG2NCACOCBNCAC0CBCG1CG2NCAC

PRO HPRO HPRO HPRO HPRO HPRO HALA HALA HALA HALA HALA HSER HSER HSER HSER HSER HSER HSER HSER HSER HSER HSER HSER HTHR HTHR HTHR HTHR HTHR HTHR HTHR HALA HALA HALA HALA HALA HVAL HVAL HVAL HVAL HVAL HVAL HVAL HASP HASP HASP H

200200200200200200201201201201201202202202202202202203203203203203203204204204204204204204205205205205205206206206206206206206207207207

-10.230-11.011-11.835-8.757-8.077-8.782-10.752-11.384-12.908-13.438-10.930-13.602-15.060-15.422-16.543-15.682-15.398-14.451-14.633-15.268-16.147-15.493-14.994-14.829-15.393-14.544-13.329-15.537-16.255-16.312-15.204-14.534-15.453-16.600-14.322-14.967-15.767-14.996-13.831-16.186-16.886-17.098-15.626-14.990-15.871

11.27010.0479.49310.94512.31412.8769.6208.4248.3167.2018.2109.4489.47510.26710.72510.17111.57610.42911.17612.51512.91910.3899.08713.22214.53015.68615.69614.74113.64615.99916.65317.84018.99519.05517.75319.90221.05322.35322.45420.94722.18919.75023.33524.64025.557

87.45387.93187.18087.21887.32088.55289.16189.70489.60789.62491.13189.48389.37188.11287.93790.59990.61087.24186.00886.25085.49685.00784.87887.28687.58587.03487.16889.11289.68789.39386.40785.88086.20285.72484.38287.03687.42087.22287.60088.92389.36989.12586.60186.47387.308

39.6641.4943.6440.6340.8540.3041.8841.9244.2247.8940.1242.0940.4538.7939.1942.0836.2236.9140.5438.4440.8240.5547.7035.0334.0733.2435.7133.8335.8234.2834.4138.9440.0742.3639.1339.6537.3037.1040.5636.5332.2638.5935.3837.0335.92

HHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH

CCOCCCNCCOCNCCOCONCCOCONCCOCOCNCCOCNCCOCCCNCC

原子原子原子原子原子原子原子原子原子原子原子原子原子原子原子原子原子原子原子原子原子原子原子原子原子原子原子原子原子原子原子原子TER原子原子原子原子原子原子原子原子原子原子原子原子

OCBCGOD1OD2NCACOCBCGCDCENZNCACOCBCGCDCENZNCACOCBCG1CG2CD1OXTNCACOCBOGNCACOCBOG1

ASP HASP HASP HASP HASP HLYS HLYS HLYS HLYS HLYS HLYS HLYS HLYS HLYS HLYS HLYS HLYS HLYS HLYS HLYS HLYS HLYS HLYS HILE HILE HILE HILE HILE HILE HILE HILE HILE HILE HSER ISER ISER ISER ISER ISER ITHR ITHR ITHR ITHR ITHR ITHR I

207207207207207208208208208208208208208208209209209209209209209209209210210210210210210210210210210777777888888

-17.040-14.957-14.115-12.921-14.656-15.319-16.095-15.655-14.567-16.005-16.852-17.728-18.601-19.805-16.488-16.140-16.346-17.343-17.057-16.780-18.026-18.408-19.364-15.398-15.507-16.341-15.920-14.079-13.188-14.210-13.895-17.41214.83416.21416.17015.10917.09118.44917.30917.38418.54219.37517.70318.969

25.74425.12424.24624.09323.68926.13227.02228.47628.82926.51227.30026.32025.50126.27129.33930.75731.36831.09031.49732.99033.80633.66634.78832.17632.81434.10634.95133.17831.94233.67630.74034.268-3.003-3.341-3.928-3.952-2.097-2.441-4.405-5.002-4.314-3.666-6.516-6.713

86.99985.01984.14484.43983.16288.36889.24489.19289.65090.69791.66492.41491.48191.12088.60988.54789.95290.59787.56287.52687.12785.68385.26890.40891.72091.54590.75192.30792.37293.75493.03192.17564.81265.27166.67867.29865.24765.50367.17768.51369.24668.61668.45867.790

39.8837.7139.4235.8948.3139.1436.6835.5834.6736.4536.2844.4735.6451.9135.3238.0736.9835.1438.4338.7642.2247.6249.9834.1334.3636.7036.9230.9625.2919.0710.9542.7341.4243.4740.8448.2840.1244.1934.1129.2626.3024.3828.9827.25

HHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHIIIIIIIIIIII

OCCOONCCOCCCCNNCCOCCCCNNCCOCCCCONCCOCONCCOCO

CG2NCACOCBNCACOCBCGCD1CD2NCACOCBCGCDNECZNH1NH2NCACOCBCGCDOE1OE2NCACOCBCGCD1CD2NCAC

THR IALA IALA IALA IALA IALA ILEU ILEU ILEU ILEU ILEU ILEU ILEU ILEU IARG IARG IARG IARG IARG IARG IARG IARG IARG IARG IARG IGLU IGLU IGLU IGLU IGLU IGLU IGLU IGLU IGLU ILEU ILEU ILEU ILEU ILEU ILEU ILEU ILEU IILE IILE IILE I

899999101010101010101011111111111111111111111212121212121212121313131313131313141414

16.60618.51219.56820.95021.93719.33021.01322.30722.75123.91422.22123.46124.70023.22421.79822.20322.75723.75820.99121.33620.12919.79818.83818.62818.07822.04622.46623.85124.69521.44820.04420.17020.72519.73924.08525.41126.47827.53225.43026.82227.52726.60926.16927.15127.462

-7.253-4.390-3.787-4.314-3.569-4.175-5.611-6.193-5.658-5.335-7.732-8.495-8.085-9.990-5.499-4.971-3.549-3.173-4.942-4.327-4.428-5.830-6.243-7.546-5.355-2.733-1.355-1.358-0.578-0.564-0.3790.1541.266-0.539-2.252-2.267-2.630-2.002-3.257-3.465-2.134-4.357-3.614-3.987-2.824

67.70270.57171.40270.95170.89272.84970.65570.23768.89168.67570.20269.68270.50169.85467.96266.67266.82766.22465.70664.34163.38863.12562.29462.11661.64067.60567.79968.46468.08868.67668.02066.63466.47965.68969.41570.08369.05368.96871.25071.89372.26973.12868.21967.19566.272

36.3421.0223.1824.1820.9221.4724.9726.5625.4319.5328.6726.0517.0724.0424.8027.7026.3921.3329.1137.8359.3577.6187.8588.8393.9426.8929.0328.5830.0431.8032.8742.1953.0556.2926.7225.1523.9423.2519.5921.1817.0225.8122.1722.1224.29

IIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIII

CNCCOCNCCOCCCCNCCOCCCNCNNNCCOCCCOONCCOCCCCNCC

328232833284328532863287328832893290329132923293329432953296329732983299330033013302330333043305330633073308330933103311331233133314331533163317331833193320332133223323332433253326

OCBCG1CG2CD1NCACOCBCGCDOE1OE2NCACOCBCGCDOE1OE2NCACOCBCGCD1CD2NCAC0CBCG1CG2NCACOCBCGOD1

ILE IILE IILE IILE IILE IGLU IGLU IGLU IGLU IGLU IGLU IGLU IGLU IGLU IGLU IGLU IGLU IGLU IGLU IGLU IGLU IGLU IGLU ILEU ILEU ILEU ILEU ILEU ILEU ILEU ILEU IVAL IVAL IVAL IVAL IVAL IVAL IVAL IASN IASN IASN IASN IASN IASN IASN I

141414141415151515151515151516161616161616161617171717171717171818181818181819191919191919

28.63026.63626.70327.47825.91826.41826.63827.50128.38425.29524.55123.13522.36922.79527.27328.10429.57530.47827.56528.46128.62327.90829.47229.82531.22131.90433.08831.27130.67530.86631.30431.12131.63832.00133.10330.54230.97030.35531.09031.32232.60233.33330.15328.96529.064

-2.545-5.195-6.427-5.405-7.632-2.123-0.9960.0440.635-0.372-1.225-0.746-1.4420.3230.2781.3150.8711.6801.6492.5813.9614.2954.734-0.397-0.866-0.791-0.550-2.277-2.476-3.925-1.516-0.991-0.9000.5740.905-1.316-0.908-2.8411.4622.9003.4144.2063.7003.6753.142

65.94666.36967.26165.14266.75665.83964.93165.59264.95164.55563.54563.33962.63363.89666.89267.54167.61567.39968.96169.83069.26468.29169.78867.92968.00966.62666.52768.52169.92170.34270.91665.57064.20264.01663.59763.17161.74163.20364.38964.24864.90664.31364.82663.92362.834

20.5022.5421.9325.418.0621.2025.5028.7827.9827.4342.0454.7758.5959.5425.3326.1928.2929.1426.3120.4832.8340.6443.5328.4227.3828.2327.7326.5522.725.486.1528.8226.0727.5328.3326.0123.1725.1726.7529.2332.0435.6625.9730.7641.11

IIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIII

OCCCCNCCOCCCOONCCOCCCOONCCOCCCCNCCOCCCNCCOCCO

332733283329333033313332333333343335333633373338333933403341334233433344334533463347334833493350335133523353335433553356335733583359336033613362336333643365336633673368336933703371

ND2NCACOCBCG1CG2CD1NCACOCBOG1CG2OXTNCACOCBNCACOCBCGCDNCACOCBCGCD1CD2NCACOCBSGNCA

ASN IILE IILE IILE IILE IILE IILE IILE IILE ITHR ITHR ITHR ITHR ITHR ITHR ITHR ITHR IALA IALA IALA IALA IALA IPRO IPRO IPRO IPRO IPRO IPRO IPRO ILEU ILEU ILEU ILEU ILEU ILEU ILEU ILEU ICYS ICYS ICYS ICYS ICYS ICYS IASN IASN I

192020202020202020212121212121212126262626262727272727272728282828282828282929292929293030

27.83032.88134.05135.34136.40433.80833.57032.62133.45635.29536.54237.02638.03036.42235.26936.27036.40943.99744.62543.71442.50644.91144.29143.46442.41142.54244.48145.85145.70041.37140.29140.81541.47039.36138.13837.43537.24340.51740.96842.48043.00540.26838.44743.16944.602

4.2302.9533.4652.7453.1883.5222.1144.4252.0911.6590.9611.1760.547-0.551-1.073-0.7971.9938.5577.7776.6226.6368.7115.6044.4664.8635.8873.4863.9515.4524.0404.2364.4113.5153.0393.1754.4511.9365.5465.8235.5815.1444.9164.9685.8945.679

64.36266.12066.80866.51466.97468.35368.91268.63370.44665.76565.46864.01663.63165.74465.08367.25763.29165.20766.32366.75466.51567.54467.40167.84568.88969.57868.43667.82967.81468.98869.95371.39371.93269.89870.77470.36870.65972.02673.40173.51274.56474.41174.41772.42572.333

36.6933.0228.4131.2136.2127.0422.4826.7422.0828.9737.1243.6141.2234.6932.3840.3555.1669.3368.3164.4362.5768.8761.8658.3952.4650.2160.5864.1561.0444.5938.3536.5533.5333.2034.4531.5037.1735.1636.1638.1039.2235.1137.7040.1439.35

IIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIII

NNCCOCCCCNCCOCOCONCCOCNCCOCCCNCCOCCCCNCCOCSNC

337233733374337533763377337833793380338133823383338433853386338733883389339033913392339333943395339633973398339934003401340234033404340534063407340834093410341134123413341434153416

COCBCGOD1ND2NCACONCACOCBOGNCACOCBCGSDCENCACOCBCG1CG2NCACOCBCGCD1CD2NE1CE2CE3CZ2CZ3CH2

ASN IASN IASN IASN IASN IASN IGLY IGLY IGLY IGLY ISER ISER ISER ISER ISER ISER IMET IMET IMET IMET IMET IMET IMET IMET IVAL IVAL IVAL IVAL IVAL IVAL IVAL ITRP ITRP ITRP ITRP ITRP ITRP ITRP ITRP ITRP ITRP ITRP ITRP ITRP ITRP I

303030303030313131313232323232323333333333333333343434343434343535353535353535353535353535

45.32945.21045.20746.71147.19447.46246.07446.82146.16446.84244.85144.16844.21844.07742.69142.65044.37944.44643.33743.03145.77746.99847.11947.78642.80541.75642.04142.95740.35539.97240.40741.23241.50040.61439.56141.34140.03238.84339.77537.85438.40240.56837.82039.98738.623

5.9497.0176.5476.3625.2337.4534.9525.0854.3804.0024.1733.5512.0381.4934.0235.3951.376-0.073-0.5070.204-0.5010.144-0.525-2.194-1.705-2.252-3.740-4.311-2.169-0.700-2.897-4.380-5.774-6.606-6.168-6.148-5.862-6.512-4.979-6.089-5.145-4.070-4.434-3.368-3.553

73.62474.20871.24471.15570.95971.33774.07575.30676.48877.43976.43377.55877.45276.37777.61277.93478.58778.66279.63980.58479.26578.59976.99577.36679.42580.24380.45179.87279.54079.38578.18781.26481.45180.55680.06082.90583.48083.20484.58184.10684.94785.29885.99286.34286.683

36.9332.0943.6455.5962.7551.8238.0339.1339.2143.7734.4732.8329.8331.0831.5334.7627.3824.3625.8226.4926.4324.8142.0017.5321.7319.2119.9721.2417.8418.1813.6820.7323.8222.1225.3026.5127.2625.0928.6329.6832.5427.2629.4333.1330.81

IIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIII

COCCONNCCONCCOCONCCOCCSCNCCOCCCNCCOCCCCNCCCCC

341734183419342034213422342334243425342634273428342934303431343234333434343534363437343834393440344134423443344434453446344734483449345034513452345334543455345634573458345934603461

NCACOCBOGNCACOCBCG1CG2CD1NCACOCBCGOD1ND2NCACOCBCGCD1CD2NCACOCBOG1CG2NCACOCBNCAC

SER ISER ISER ISER ISER ISER IILE IILE IILE IILE IILE IILE IILE IILE IASN IASN IASN IASN IASN IASN IASN IASN ILEU ILEU ILEU ILEU ILEU ILEU ILEU ILEU ITHR ITHR ITHR ITHR ITHR ITHR ITHR IALA IALA IALA IALA IALA IGLY IGLY IGLY I

363636363636373737373737373738383838383838383939393939393939404040404040404141414141424242

41.05740.30639.08339.00141.21141.75038.11936.99237.41838.24135.71435.92335.23734.69936.86037.29036.21036.40638.06139.21640.13139.17335.06434.00932.92732.73933.36034.30633.52334.96332.21531.09029.93529.22730.56530.40531.52029.75728.68328.90330.01228.52227.83127.86428.773

-7.830-8.723-9.330-9.447-9.882-10.425-9.702-10.426-11.897-12.177-10.086-9.994-8.686-9.222-12.821-14.232-15.281-16.244-14.611-13.645-13.509-12.956-15.116-16.109-15.725-14.539-16.349-16.668-16.640-18.037-16.739-16.516-15.952-15.040-17.848-18.854-18.325-16.503-16.071-14.655-14.303-17.069-13.862-12.495-11.607

80.32879.46380.13281.35079.04180.24479.31579.84179.61378.73779.09477.62079.51776.96280.36180.22579.95779.18881.51281.79680.97582.94980.58980.46979.51679.22681.84082.98684.31682.72479.02878.13778.95378.50877.50378.53676.43280.14581.03381.59982.03182.18981.58282.10081.290

22.0822.4622.6524.3821.3529.0822.9525.3626.8429.2725.0434.6230.6430.5930.3434.9735.1037.3639.3850.5856.2656.0732.5830.5030.4629.7031.8435.6045.4439.9132.1136.9236.6841.3638.8744.5138.4134.4635.7933.4231.3737.1428.1826.1625.89

IIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIII

NCCOCONCCOCCCCNCCOCCONNCCOCCCCNCCOCOCNCCOCNCC

346234633464346534663467346834693470347134723473347434753476347734783479348034813482348334843485348634873488348934903491349234933494349534963497349834993500350135023503350435053506

ONCACOCBCGSDCENCACOCBCGCD1CD2CE1CE2CZOHNCACOCBSGNCACOCBNCACOCBNCACOCBCGCD1CD2

GLY IMET IMET IMET IMET IMET IMET IMET IMET ITYR ITYR ITYR ITYR ITYR ITYR ITYR ITYR ITYR ITYR ITYR ITYR ICYS ICYS ICYS ICYS ICYS ICYS IALA IALA IALA IALA IALA IALA IALA IALA IALA IALA ILEU ILEU ILEU ILEU ILEU ILEU ILEU ILEU I

424343434343434343444444444444444444444444454545454545464646464647474747474848484848484848

29.33828.93229.83529.51430.42229.86330.87630.92729.43128.22827.92028.34928.94826.44025.87826.26324.95225.73324.41524.82424.32028.04828.45029.96730.51527.92826.11630.66532.12832.73233.70532.74632.20032.68432.45733.30531.92731.28731.01432.04132.58929.58229.21629.31927.771

-10.675-11.910-11.125-9.613-8.806-11.691-10.946-11.571-10.913-9.239-7.799-7.096-6.028-7.549-8.026-7.427-9.061-7.842-9.498-8.867-9.249-7.724-7.120-7.059-6.076-7.903-7.936-8.135-8.093-7.009-6.368-9.518-6.861-5.845-4.476-3.602-5.952-4.290-2.995-2.745-1.653-3.040-1.822-0.520-2.056

81.81180.00379.16779.08979.07277.72676.82375.10274.58078.96778.84380.12480.08878.65577.35076.15477.31574.94776.10074.92273.69081.24582.51082.63183.11383.68983.88382.26782.34881.43281.79481.98380.21679.28679.89679.81377.92780.48181.14582.29282.43881.72782.64281.85483.235

23.8527.0626.4925.6324.7025.0931.8750.3649.8323.5621.8619.9923.3923.8425.7125.8027.2827.0122.7525.0122.7517.0917.8216.2521.2115.2420.7318.6617.7119.9120.2315.3523.6222.1221.7818.9418.6521.7021.0321.1816.6121.7013.059.0515.13

IIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIII

ONCCOCCSCNCCOCCCCCCCONCCOCSNCCOCNCCOCNCCOCCCC

350735083509351035113512351335143515351635173518351935203521352235233524352535263527352835293530353135323533353435353536353735383539354035413542354335443545354635473548354935503551

NCACOCBCGCDOE1OE2NCACOCBOGNCACOCBCGCD1CD2NCACOCBCG1CG2CD1NCACOCBCGOD1ND2NCACOCBCG1

GLU IGLU IGLU IGLU IGLU IGLU IGLU IGLU IGLU ISER ISER ISER ISER ISER ISER ILEU ILEU ILEU ILEU ILEU ILEU ILEU ILEU IILE IILE IILE IILE IILE IILE IILE IILE IASN IASN IASN IASN IASN IASN IASN IASN IVAL IVAL IVAL IVAL IVAL IVAL I

494949494949494949505050505050515151515151515152525252525252525353535353535353545454545454

32.25533.20334.60135.33533.22631.98431.98732.93331.07834.97336.30736.36837.23536.68437.98835.39935.37434.99435.37134.42135.01434.00236.27134.32633.92735.16135.13332.98132.25333.78931.21236.27237.49338.21139.13838.45937.91437.31138.06837.78138.47138.20437.06238.06438.791

-3.767-3.663-3.275-2.512-5.012-5.184-4.123-4.160-3.244-3.759-3.428-2.022-1.228-4.412-4.119-1.714-0.4360.7981.923-0.552-1.455-1.641-0.7870.5821.7322.3943.5741.2722.4930.5203.1051.6492.2433.1843.8871.1570.3850.977-0.9413.2414.1315.5915.9873.8324.820

83.10884.25883.78684.43985.03185.96887.04087.84387.07382.61182.08281.49281.84880.95680.51880.61879.91380.75480.41278.68677.58576.48376.97281.87582.72583.30483.72683.89784.53884.97183.59783.37483.92382.99983.43184.35885.51186.43485.46781.73380.78481.10181.20679.30678.352

20.1819.6320.5526.9017.0420.1422.5221.5710.2918.3918.0418.3819.6916.4114.6819.3417.7119.4621.2116.1711.297.0414.5718.0416.9317.4022.3217.8121.789.738.9822.0021.4821.8823.9518.1629.8931.8841.9423.8325.4529.8231.4920.9411.51

IIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIII

NCCOCCCOONCCOCONCCOCCCCNCCOCCCCNCCOCCONNCCOCC

355235533554355535563557355835593560356135623563356435653566356735683569357035713572357335743575357635773578357935803581358235833584358535863587358835893590359135923593359435953596

CG2NCACOCBOGNCACONCACOCBSGNCACOCBOGNCACOCBNCACOCBCG1CG2CD1NCACOCBCGCDOE1OE2

VAL ISER ISER ISER ISER ISER ISER IGLY IGLY IGLY IGLY ICYS ICYS ICYS ICYS ICYS ICYS ISER ISER ISER ISER ISER ISER IALA IALA IALA IALA IALA IILE IILE IILE IILE IILE IILE IILE IILE IGLU IGLU IGLU IGLU IGLU IGLU IGLU IGLU IGLU I

545555555555555656565657575757575758585858585859595959596060606060606060616161616161616161

38.45339.27839.16939.53940.39640.11240.10138.88039.23138.95839.63637.95837.67836.19235.35438.06438.04035.86134.44933.95032.74334.24135.14934.84534.35133.72332.94435.47334.08433.56332.32631.71934.69334.42934.77034.78831.91630.78629.50128.84430.53029.64729.43730.45328.268

2.3856.3747.7978.6468.2798.1619.5709.77410.70410.27610.7229.4308.9889.1698.2957.5357.00710.29810.5169.5079.21011.95712.2748.9287.9926.6996.0477.6256.3095.0645.2574.2924.3822.8735.0072.1396.5046.7136.0145.3878.2168.4359.89510.57510.350

78.97581.25881.56680.38379.55382.72482.95780.26779.20577.77476.85177.56476.19675.86776.12876.04074.29075.25774.94873.89173.80274.46173.40473.10472.05872.58371.86571.10873.80474.40475.28075.75375.26875.38376.68274.12475.48676.37675.94976.74776.57677.79978.12178.44378.034

17.8933.8934.1933.5237.9135.5853.8628.5828.0529.9730.9527.6224.7726.2727.5824.7428.6622.2018.1018.9920.2013.5917.5820.4320.5823.2524.0717.6925.0925.8125.4429.1426.4829.2427.6835.8627.5828.0923.6422.2728.6756.1479.3187.3578.03

IIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIII

CNCCOCONCCONCCOCSNCCOCONCCOCNCCOCCCCNCCOCCCOO

359735983599360036013602360336043605360636073608360936103611361236133614361536163617361836193620362136223623362436253626362736283629363036313632363336343635363636373638363936403641

NCACOCBCGCDCENZNCACOCBOG1CG2NCACOCBCGCDOE1NE2NCACOCBCGCDNECZNH1NH2NCACOCBCGSDCEN

LYS ILYS ILYS ILYS ILYS ILYS ILYS ILYS ILYS ITHR ITHR ITHR ITHR ITHR ITHR ITHR IGLN IGLN IGLN IGLN IGLN IGLN IGLN IGLN IGLN IARG IARG IARG IARG IARG IARG IARG IARG IARG IARG IARG IMET IMET IMET IMET IMET IMET IMET IMET ILEU I

626262626262626262636363636363636464646464646464646565656565656565656565666666666666666667

29.15627.94128.01527.04927.72426.41626.21825.05024.80529.15429.30929.10528.44130.70230.80730.91729.66629.43927.94427.47630.19431.71232.34331.65633.61727.21225.80224.99824.03525.31925.93525.51426.06325.58724.54226.17025.39024.68324.91023.99825.10624.55725.32523.84626.138

6.1105.4853.9603.3485.7885.2555.8705.2425.9853.3501.9141.5940.6331.4541.607-0.0292.4142.1232.1271.3013.1233.1314.3075.2904.1843.0773.2422.1201.6204.5875.7317.1038.1538.4577.8009.4171.6950.574-0.730-1.5240.4301.5571.4431.367-0.951

74.67574.23074.46074.91372.74972.17970.78970.03568.77074.15774.39075.88076.23773.93272.49874.28476.78678.19578.57079.33479.10478.91279.68579.95880.08178.00278.26877.65378.26477.71478.48277.92578.79379.99480.47580.71876.45375.84976.61676.82974.38873.50271.84070.84177.060

22.1021.5922.5025.7625.1923.6240.5937.3437.4617.7216.7919.1018.8019.1424.8416.7718.3818.2617.3217.6314.9621.1920.9726.3216.1716.6918.0520.8521.7717.4927.2536.1749.2741.7030.9044.9920.2316.6515.7517.2919.3027.3324.8024.0917.99

IIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIII

NCCOCCCCNNCCOCOCNCCOCCCONNCCOCCCNCNNNCCOCCSCN

364236433644364536463647364836493650365136523653365436553656365736583659366036613662366336643665366636673668366936703671367236733674367536763677367836793680368136823683368436853686

CACOCBCGCD1CD2NCACOCBOGNCACONCACOCBCGCD1CD2CE1CE2CZNCACOCBSGNCACOCBCGCDNCACO

LEU ILEU ILEU ILEU ILEU ILEU ILEU ISER ISER ISER ISER ISER ISER IGLY IGLY IGLY IGLY IPHE IPHE IPHE IPHE IPHE IPHE IPHE IPHE IPHE IPHE IPHE ICYS ICYS ICYS ICYS ICYS ICYS IPRO IPRO IPRO IPRO IPRO IPRO IPRO IHIS IHIS IHIS IHIS I

676767676767676868686868686969696970707070707070707070707171717171717272727272727273737373

26.41825.65825.18427.94728.75530.27628.44125.52524.77723.30622.65624.87926.22922.78821.42221.29020.27922.32422.26522.52322.03423.34622.94723.43322.12123.08621.75722.24423.29923.61323.28824.20925.11825.68122.00421.61521.84922.04120.12419.66020.82521.84422.08923.38123.562

-2.129-2.015-3.016-2.218-2.694-2.561-4.176-0.799-0.628-1.021-1.4630.8341.168-0.863-1.229-2.746-3.242-3.495-4.948-5.477-6.564-5.574-5.624-4.685-6.634-4.746-6.719-5.766-4.720-5.186-4.039-3.472-5.443-5.978-3.667-2.570-2.796-1.806-2.345-3.743-4.260-4.066-4.412-5.238-6.213

77.88079.22679.79978.13676.90777.27576.51579.74580.99480.84881.80681.48181.81679.63679.31079.35579.80078.88978.94780.37080.75778.01976.57075.68376.11574.29774.73273.84181.15982.51183.51184.08882.61284.26883.65684.56386.06386.80484.20183.87483.00686.50287.88887.94687.207

16.8716.2319.2918.9918.8415.2815.1113.3316.3319.3121.4015.4224.1817.7813.1815.7114.0717.9818.2818.4818.8118.9919.1713.8614.0215.7821.4819.9815.7219.2519.5417.7217.6322.2720.4320.5618.3518.4520.0322.0922.4119.4719.6621.6825.46

IIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIII

CCOCCCCNCCOCONCCONCCOCCCCCCCNCCOCSNCCOCCCNCCO

368736883689369036913692369336943695369636973698369937003701370237033704370537063707370837093710371137123713371437153716371737183719372037213722372337243725372637273728372937303731

CBCGND1CD2CE1NE2NCACOCBCGCDCENZNCACOCBCG1CG2NCACOCBOGNCACOCBNCACONCACOCBOGNCA

HIS IHIS IHIS IHIS IHIS IHIS ILYS ILYS ILYS ILYS ILYS ILYS ILYS ILYS ILYS IVAL IVAL IVAL IVAL IVAL IVAL IVAL ISER ISER ISER ISER ISER ISER IALA IALA IALA IALA IALA IGLY IGLY IGLY IGLY ISER ISER ISER ISER ISER ISER ISER ISER I

737373737373747474747474747474757575757575757676767676767777777777787878788181818181818282

20.90019.67219.30418.77018.22217.87824.27525.55825.41424.52826.40627.91128.75128.59729.43826.29126.31527.65328.59026.10624.73727.25127.74229.01030.11029.92628.84630.12631.25432.37532.94333.41233.47832.89533.41234.88235.56339.94741.29342.34843.50141.17240.42341.95642.867

-5.199-4.351-3.876-3.846-3.109-3.082-4.823-5.460-6.919-7.310-4.771-5.064-4.501-5.307-4.661-7.728-9.147-9.491-8.668-9.983-9.626-9.701-10.679-11.098-11.307-12.056-12.402-12.787-10.652-10.766-12.175-12.653-9.766-12.843-14.198-14.206-13.090-16.327-16.933-16.541-16.954-18.457-18.891-15.751-15.344

88.48588.70389.94387.82089.81188.54088.82488.93589.27490.04490.03089.90891.09692.38393.45988.69288.98789.62989.63387.71587.12286.66790.22790.83989.79388.83291.62692.12089.98289.04889.03488.00389.41490.17990.23989.84990.29192.12192.34891.30991.42192.36893.49290.31089.249

20.8322.2316.7624.2016.4115.3921.9521.3523.8922.2822.8221.5016.8615.5828.7730.2432.2533.2536.6731.7130.9637.2738.7543.3845.2041.7145.3551.2449.6754.4757.4259.5051.6460.1362.6963.5563.7667.8165.1461.1860.4165.7069.3656.7051.54

IIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIII

CCNCCNNCCOCCCCNNCCOCCCNCCOCONCCOCNCCONCCOCONC

373237333734373537363737373837393740374137423743374437453746374737483749375037513752375337543755375637573758375937603761376237633764376537663767376837693770377137723773377437753776

COCBOGNCACOCBCGCD1CD2NCACOCBCGND1CD2CE1NE2NCACOCBCG1CG2NCACOCBCGCDNECZNH1NH2NCACOCB

SER ISER ISER ISER ILEU ILEU ILEU ILEU ILEU ILEU ILEU ILEU IHIS IHIS IHIS IHIS IHIS IHIS IHIS IHIS IHIS IHIS IVAL IVAL IVAL IVAL IVAL IVAL IVAL IARG IARG IARG IARG IARG IARG IARG IARG IARG IARG IARG IASP IASP IASP IASP IASP I

828282828383838383838383848484848484848484848585858585858586868686868686868686868787878787

43.68543.15542.06742.94444.99245.83945.83545.82847.28748.27947.93949.69145.87245.97444.62844.59246.85048.15749.14848.63550.18049.89443.53642.20241.92841.26941.11241.12239.76542.42442.18143.40143.43541.58640.08939.46139.54638.73137.74638.89644.40945.58245.11844.44146.690

-14.090-12.987-15.117-14.947-14.262-13.152-11.917-10.799-13.614-12.574-12.173-13.159-12.145-11.040-10.553-9.730-11.516-12.110-11.364-13.377-12.144-13.372-11.067-10.744-9.272-8.945-11.325-10.639-11.211-8.378-6.974-6.217-4.977-6.355-6.712-6.267-7.320-8.386-8.587-9.253-6.944-6.265-5.630-6.299-7.243

89.61089.72787.96686.86889.78290.18289.26489.74890.31090.83892.29590.75087.95786.98386.42585.52585.82086.25086.84986.16987.12386.72186.97886.47186.18985.19487.40588.75386.75187.02286.79486.29086.31988.07488.21789.53490.56590.65489.78491.64785.79085.27183.96483.19284.879

47.0344.4052.8862.1340.8533.2632.9430.6629.3527.0912.1624.4229.8229.5429.7325.1926.3228.4529.8824.7430.4621.4032.0732.0633.8436.0533.3827.1937.6932.5431.6131.9135.2328.4041.9446.7763.9866.0452.0762.2630.3432.4031.3030.0234.02

IIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIII

COCONCCOCCCCNCCOCCNCCNNCCOCCCNCCOCCCNCNNNCCOC

377737783779378037813782378337843785378637873788378937903791379237933794379537963797379837993800380138023803380438053806380738083809381038113812381338143815381638173818381938203821

CGOD1OD2NCACOCBOG1CG2NCACOCBNCACOCBCG1CG2CD1NCACOCBCGCDOE1OE2NCACOCBCG1CG2NCACOCBN

ASP IASP IASP ITHR ITHR ITHR ITHR ITHR ITHR ITHR IALA IALA IALA IALA IALA IILE IILE IILE IILE IILE IILE IILE IILE IGLU IGLU IGLU IGLU IGLU IGLU IGLU IGLU IGLU IVAL IVAL IVAL IVAL IVAL IVAL IVAL IALA IALA IALA IALA IALA IALA I

878787888888888888888989898989909090909090909091919191919191919192929292929292939393939394

47.46347.14548.40645.51645.06346.07546.94244.82246.02743.76745.96846.95546.44847.20547.56445.20344.67544.39943.79643.30943.43942.78044.55444.80244.50142.98342.36945.25546.76147.50148.72546.85342.37440.93940.52339.57140.42838.92340.62241.24140.90140.85339.94941.90341.832

-7.838-7.582-8.554-4.392-3.748-3.950-3.091-2.258-1.671-2.090-5.085-5.362-5.308-5.591-6.708-4.897-4.930-3.493-2.739-5.690-7.060-5.835-7.915-3.115-1.768-1.709-2.675-1.470-1.457-1.542-1.840-1.312-0.559-0.475-0.874-1.6030.9250.9681.268-0.393-0.747-2.249-2.781-0.116-2.953

86.08687.26085.74183.68782.44381.32181.05882.70383.17983.78280.63979.60878.19277.28279.85977.97576.61876.19176.94976.59077.25175.17876.69574.99274.51374.24173.78573.20173.38372.05472.07470.99774.50874.30072.88872.70174.57474.19876.07671.88970.52170.32069.63169.56170.883

38.1932.9032.5730.8631.2031.7433.7529.8136.5424.4231.6030.0029.6832.5635.6626.6721.5220.0218.8022.5627.8220.2523.9722.4825.0225.2524.4026.6543.5266.8571.4376.3320.3922.5224.0922.6024.9323.9329.4023.1420.9021.9722.7417.9620.31

IIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIII

COONCCOCOCNCCOCNCCOCCCCNCCOCCCOONCCOCCCNCCOCN

382238233824382538263827382838293830383138323833383438353836383738383839384038413842384338443845384638473848384938503851385238533854385538563857385838593860386138623863386438653866

CACOCBNCACOCBCGCD1CD2CE1CE2CZNCACOCBCG1CG2NCACOCBNCACOCBCGOD1OD2NCACOCBCGCD1CD2NCA

ALA IALA IALA IALA IPHE IPHE IPHE IPHE IPHE IPHE IPHE IPHE IPHE IPHE IPHE IVAL IVAL IVAL IVAL IVAL IVAL IVAL IALA IALA IALA IALA IALA IASP IASP IASP IASP IASP IASP IASP IASP ILEU ILEU ILEU ILEU ILEU ILEU ILEU ILEU ILEU ILEU I

94949494959595959595959595959596969696969696979797979798989898989898989999999999999999100100

41.88340.76440.14043.27640.48339.42638.07237.28439.35238.25338.50936.93937.47535.91436.17237.81436.53436.41235.35836.35435.08636.16437.50637.46737.13236.35338.80737.70937.42535.97935.28338.38238.09438.60237.29635.54034.15833.25432.30233.83232.38931.97832.32533.54532.711

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70.72871.48470.99871.18772.67273.47972.75072.71574.80575.69576.70775.51777.55476.34677.36072.18671.49970.19169.86271.20870.31372.52669.45268.23568.56767.88667.51569.62770.05070.55870.29471.18071.74971.27172.77871.33871.84970.61170.57572.65573.16373.98173.96669.62868.426

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75.38995.18999.08085.26085.99795.99589.92899.98298.319101.110107.85282.550121.849125.264124.405100.35889.62092.259111.05184.59297.44296.76689.95684.23895.885100.49989.166103.250108.041114.04372.820105.88698.647101.69287.587100.193103.614112.88292.709115.192117.43486.45586.66380.584102.723

1.001.001.001.001.001.001.001.001.001.001.001.001.001.001.001.001.001.001.0011.001.001.001.001.001.001.001.001.001.001.001.001.001.001.001.001.001.001.001.001.001.001.001.001.001.00

40.1932.3942.0331.0020.4351.5253.0239.5140.1850.6746.9834.5538.4935.9140.2240.8932.9548.5202.3831.1720.3026.7530.2947.9643.1226.1741.0624.8733.9741.8824.8642.4629.7846.7238.2238.6941.7645.8540.4340.5232.0349.4743.8448.1845.47

WWWWWWWWWWWWWWWWWWWWWWWWWWWWWWWWWWWWWWWWWWWWW

OOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOO

427242734274427542764277427842794280428142824283428442854286428742884289429042914292429342944295429642974298429943004301430243034304430543064307430843094310431143124313431443154316

OOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOO

344345346347348349350351352353354355356357358359360361362363364365366367368369370371372373374375376377378379380381382383384385386387388

14.2705.3035.88413.76628.817-16.20112.538-11.93014.8484.331-30.1880.83139.804-5.193-4.3182.4045.6334.540-19.66046.22523.30117.09926.600-22.5200.31320.61322.77114.20932.180-15.578-5.8065.261-26.827-0.39238.359-8.69734.32925.046-12.30722.34620.14517.103-19.79914.6657.042

31.2145.46614.859-10.804-6.6384.01212.93440.33722.83311.52027.12337.120-9.14341.09215.66030.953-10.209-6.16712.268-3.46428.53311.4102.35139.59525.144-10.1826.260-9.494-13.18222.30233.72941.52427.79820.7083.116-6.590-8.4384.2064.8120.99933.49317.60434.57336.49935.670

111.26773.31694.56994.63995.408101.225104.399106.636108.10483.240112.476115.46367.597118.29694.91094.99696.938100.513100.88488.101108.032108.574110.176116.26194.62477.98679.455101.67964.680119.158119.651122.29495.62696.95487.84090.18663.764109.06890.954109.24494.808111.48691.860114.33494.968

53.2335.9734.3637.5546.0555.3650.3734.7132.5865.3054.9545.1438.0749.3864.7743.8133.8239.6627.4043.3749.2847.1237.3849.4740.9237.7247.2350.8631.9067.2278.8364.7952.3947.0951.4637.8243.1536.8554.8355.8333.8558.3230.2875.5648.07

WWWWWWWWWWWWWWWWWWWWWWWWWWWWWWWWWWWWWWWWWWWWW

OOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOO

431743184319432043214322432343244325432643274328432943304331433243334334433543364337433843394340434143424343434443454346434743484349435043514352435343544355435643574358435943604361

OOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOO

389390391392393394395396397398399400401402403404405406407408409410411412413414415416417418419420421422423424425426427428429430431432433

32.24510.28334.895-25.110-25.38911.89045.837-8.379-2.21521.86924.0284.868-13.446-14.032-8.252-19.61843.024-8.28013.3861.781-19.493-12.357-16.3969.25926.4523.62915.2261.142-8.71514.67141.3148.05729.70818.10220.15818.73924.78333.41035.00413.65131.90220.41332.92417.14317.696

-16.17821.0587.44716.20434.70821.970-5.82440.1880.600-8.1338.82130.4320.54930.27225.3767.134-2.57339.609-2.161-3.49633.56032.93041.45322.38310.63826.00413.84427.13222.235-10.4287.42517.8007.4904.68913.01414.99924.390-5.505-3.76618.89810.93614.82922.61427.06829.224

70.702100.027103.148100.371117.495101.82089.349104.60881.68289.554110.40791.49894.109124.462115.71997.10887.596100.109101.13873.915127.41284.450106.252107.628108.233108.63773.00293.054116.59790.69277.188101.96170.081108.132111.569112.142107.69995.20395.19290.82083.76881.65295.00492.21790.849

49.0184.1740.3550.3148.6668.2828.5550.7155.9170.3840.6763.3038.5567.3372.0469.7447.0645.2240.3235.1052.1255.6367.7862.6755.7532.7048.6041.4846.4944.7658.4651.8936.1965.8856.6976.6468.9242.3835.8944.9450.7786.2557.2341.9444.20

WWWWWWWWWWWWWWWWWWWWWWWWWWWWWWWWWWWWWWWWWWWWW

OOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOO

436243634364436543664367436843694370437143724373437443754376437743784379438043814382438343844385438643874388438943904391439243934394439543964397439843994400440144024403440444054406

OOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOO

434435436437438439440441442443444445446447448449450451452454455456457458459460461462463464465466467468469470471472473474475476477478479

6.23515.36812.35217.216-24.4676.899-5.836-17.656-21.78139.86042.143-8.339-5.43910.11416.23912.93115.03310.617-5.587-2.6943.2416.6664.91213.17725.78622.63517.322-7.22435.61129.88331.809-4.26010.39625.26338.24836.347-16.914-9.18440.72631.80816.1883.50911.28936.903-6.947

13.9091.7452.448-1.65421.96437.19725.47123.63021.6666.3468.359-3.324-2.5069.300-12.46714.96216.02515.90514.18914.14825.41928.24826.58132.16435.9214.63837.39420.70311.671-13.953-8.8227.67024.91511.0715.4429.34141.48224.2641.808-18.64222.8582.53641.122-5.0448.034

97.039105.621102.309103.17197.052100.238114.752116.338113.53767.02169.50088.58984.631105.29979.69582.73283.69883.86196.63788.813113.47294.111118.595114.12798.72574.051105.719114.85198.38262.90291.81489.71391.43282.71699.845100.618111.14181.84966.83370.728110.296103.295108.94364.03891.049

36.2565.4556.9064.2559.1753.3449.1460.4830.8232.0139.7148.5949.0755.0648.8155.9755.4954.7117.1939.3835.5931.2033.1257.3658.9946.0631.0939.3046.5257.0248.9547.1840.3554.1542.8134.6542.0047.3043.7237.5949.7742.8445.9855.2152.73

WWWWWWWWWWWWWWWWWWWWWWWWWWWWWWWWWWWWWWWWWWWWW

OOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOO

原子原子原子原子原子原子原子原子原子原子原子原子原子原子原子原子原子原子原子原子原子原子原子原子原子原子原子原子原子原子原子TER

44074408440944104411441244134414441544164417441844194420442144224423442444254426442744284429443044314432443344344435443644374438

OOOOOOOOOOOOOOOOOOOOOOOOOOOOOOO

HOH WHOH WHOH WHOH WHOH WHOH WHOH WHOH WHOH WHOH WHOH WHOH WHOH WHOH WHOH WHOH WHOH WHOH WHOH WHOH WHOH WHOH WHOH WHOH WHOH WHOH WHOH WHOH WHOH WHOH WHOH WHOH W

480481482483484485486487488489490491492493494495496497498499500501502503504505506507508509510510

29.751-19.53713.21349.56820.13823.47717.274-3.839-9.415-1.3879.922-19.2825.00417.415-12.983-7.15937.9916.6980.53740.928-9.156-33.29714.744-0.797-4.02139.144-4.75528.66826.1221.611-16.935

-15.58840.486-5.095-7.87010.49420.57623.44323.92430.7609.782-7.53613.51029.828-8.22320.33022.883-8.46822.51527.673-10.55436.94921.816-12.29613.710-6.785-0.596-6.160-12.917-13.358-7.78338.862

72.186107.19567.72076.168110.659109.91092.256116.158123.63678.99774.819103.37493.74791.913105.53983.76895.150106.54090.15882.99184.009110.51683.50092.43782.55689.05485.44186.01385.255103.50097.751

1.001.001.001.001.001.001.001.001.001.001.001.001.001.001.001.001.001.001.001.001.001.001.001.001.001.001.001.001.001.001.00

39.7744.1960.9056.8851.3540.5920.5653.0352.6253.8356.1542.4945.3437.1854.5746.6250.2431.6749.7367.7872.9549.3861.0367.4366.4260.5149.2572.2054.4963.2138.07

WWWWWWWWWWWWWWWWWWWWWWWWWWWWWWW

OOOOOOOOOOOOOOOOOOOOOOOOOOOOOOO

^a根据表6及7中所示的Chothia编号系统(Al-Lazikani等人，Jour.Mol.Biol. 273：927-948，1997)分别编号轻链(L)和重链(H)的氨基酸残基。IL-13(I)的氨基酸残基编号如SEQ ID NO：4所示(图2B)。

^b各栏根据Protein Data Bank Format，2.2版标记柱。

表12.人IL-13/mAb13.2Fab/IL-13Rα1的结构坐标^a，b

	#	名称	残基链	残基#	X	Y	Z	occ	B	SegID	Ele
	#	名称	残基链	残基#	X	Y	Z	occ	B	SegID	Ele	原子原子原子原子原子原子原子原子原子原子原子原子原子原子原子原子原子原子原子原子原子原子原子原子原子原子原子原子原子原子原子原子原子原子原子原子原子原子原子原子原子	1234567891011121314151617181920212223242526272829303132333435363738394041	CBCGCONCDCANCACBOGCONCACBOG1CG2CONCACBCONCACBCGCD1CD2CONCACBCGCDNECZNH1	PRO IPRO IPRO IPRO IPRO IPRO IPRO ISER ISER ISER ISER ISER ISER ITHR ITHR ITHR ITHR ITHR ITHR ITHR IALA IALA IALA IALA IALA ILEU ILEU ILEU ILEU ILEU ILEU ILEU ILEU IARG IARG IARG IARG IARG IARG IARG IARG I	666666677777788888889999910101010101010101111111111111111	27.01625.92728.49428.95526.03725.35527.16929.15830.31431.59432.43330.43829.80731.23831.54231.05531.60229.52533.04933.86633.45534.88635.09935.60136.74034.89635.45834.53235.16136.66334.53335.64136.70334.54434.60533.26833.16832.05632.24831.35230.187	30.54430.35628.57127.65828.38828.90229.25029.10228.39928.86627.73228.62729.50527.76027.92426.65925.52626.58528.09827.69228.70328.84429.36527.49927.42026.42525.08224.13322.75122.83721.98724.59724.13624.64324.15024.45323.82824.46624.16523.35023.118	-8.876-7.827-9.333-10.011-9.357-8.177-9.667-8.292-7.754-8.450-8.694-6.254-5.678-5.628-4.220-3.518-4.191-3.602-4.021-4.837-2.891-2.652-1.233-2.836-3.303-2.407-2.467-1.702-1.483-1.178-0.316-3.910-4.306-4.689-6.058-6.736-8.127-8.967-10.388-10.973-10.391	1.001.001.001.001.001.001.001.001.001.001.001.001.001.001.001.001.001.001.001.001.001.001.001.001.001.001.001.001.001.001.001.001.001.001.001.001.001.001.001.001.00	78.9479.1177.0478.7579.0378.5777.8173.9270.4671.6870.9868.5768.8264.8561.3560.2160.1660.4759.3960.3656.2953.2453.7250.0848.7747.4847.1247.1247.8246.7547.4145.9444.3145.7447.0650.4755.2359.6664.2667.0167.52	IIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIII	CCCONCCNCCOCONCCOCCONCCCONCCCCCCONCCCCNCN

NH2CONCACBCGCDOE1OE2CONCACBCGCD1CD2CONCACBCG2CG1CD1CONCACBCGCDOE1OE2CONCACBCGCDOE1OE2C

ARG IARG IARG IGLU IGLU IGLU IGLU IGLU IGLU IGLU IGLU IGLU ILEU ILEU ILEU ILEU ILEU ILEU ILEU ILEU IILE IILE IILE IILE IILE IILE IILE IILE IGLU IGLU IGLU IGLU IGLU IGLU IGLU IGLU IGLU IGLU IGLU IGLU IGLU IGLU IGLU IGLU IGLU I

111111121212121212121212131313131313131314141414141414141515151515151515151616161616161616

31.63835.75036.51735.82336.86336.65435.29835.34936.41234.31238.26139.20538.39539.68539.62340.90242.13640.85540.03541.14639.04539.27637.97838.09037.73136.37139.70840.55839.07039.36938.37236.96936.11534.89636.67640.81441.51441.25242.66542.89544.38444.95444.25546.10543.630

22.79124.79324.13426.13526.84328.34628.81928.90029.17928.70026.43626.34126.23325.79025.78825.24026.05425.23824.38924.10323.48522.12521.33219.99621.02220.36822.11521.34022.99423.01523.94323.34024.05623.95824.69823.43422.83924.51024.89126.16526.47527.03127.02227.46723.796

-12.151-6.845-7.533-6.761-7.497-7.313-7.850-9.359-9.898-9.988-7.031-7.804-5.707-5.186-3.657-3.027-3.419-1.496-5.688-6.105-5.597-6.074-5.907-6.653-4.430-4.199-7.542-7.968-8.334-9.761-10.458-10.484-11.508-11.425-12.394-10.041-10.850-9.359-9.466-8.650-8.463-9.751-10.754-9.741-9.001

66.6746.5547.1146.2845.5246.3849.2651.6054.4053.8143.9544.0243.0343.2141.9143.1040.0843.8544.0544.3244.0644.7842.0541.6739.8838.7947.2047.5948.8551.7653.3657.8161.6063.7464.2452.1753.3352.9052.5553.3954.5856.4756.9356.7151.84

IIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIII

NCONCCCCOOCONCCCCCCONCCCCCCONCCCCOOCONCCCCOOC

ONCACBCGCD1CD2CONCACBCG1CG2CONCACBCGOD1ND2CONCACBCG2CG1CD1CONCACBOG1CG2CONCACBCGCDOE1

GLU ILEU ILEU ILEU ILEU ILEU ILEU ILEU ILEU IVAL IVAL IVAL IVAL IVAL IVAL IVAL IASN IASN IASN IASN IASN IASN IASN IASN IILE IILE IILE IILE IILE IILE IILE IILE ITHR ITHR ITHR ITHR ITHR ITHR ITHR IGLN IGLN IGLN IGLN IGLN IGLN I

161717171717171717181818181818181919191919191919202020202020202021212121212121222222222222

44.65543.32344.19343.65843.93343.90745.30344.28745.32643.13443.14341.70741.69140.85544.01644.77943.86544.58744.24344.46345.44443.49146.10646.76046.68148.13348.59848.08148.08148.50748.66549.84647.76648.27247.51546.11047.93448.14948.38647.71747.79647.56346.10746.03846.743

23.52323.18722.10721.56222.50421.77823.19020.98820.36920.69919.73919.56218.68618.90420.24119.50821.53722.07223.55323.97324.63723.59921.87421.38622.30122.23323.17024.60122.69523.64920.80420.52719.88418.53617.93418.11918.63417.60116.40418.15617.34418.24218.69619.89120.011

-9.623-7.842-7.389-6.071-4.894-3.551-4.990-8.437-8.649-9.068-10.170-10.669-11.919-9.603-11.309-11.927-11.615-12.767-12.930-14.361-14.697-15.222-12.654-13.559-11.506-11.369-10.239-10.471-8.882-7.757-11.140-11.286-10.725-10.475-9.292-9.493-7.998-11.686-11.597-12.833-14.039-15.257-15.411-16.340-17.331

50.1653.8554.8555.5357.9358.0455.2154.6453.2954.6756.0255.6754.3654.2656.8156.4958.6660.2462.7766.3066.8769.0460.7661.6760.6661.3159.8959.0858.3553.9962.2462.8264.1367.0565.0165.2064.1369.9470.1674.8479.5679.6982.1584.3785.68

IIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIII

ONCCCCCCONCCCCCONCCCONCONCCCCCCONCCOCCONCCCCO

NE2CONCACBCGOD1ND2CONCACBCGOD1ND2CONCACBCGCDCENZCONCACBCONCDCACBCGCONCACBCGCD1

GLN IGLN IGLN IASN IASN IASN IASN IASN IASN IASN IASN IASN IASN IASN IASN IASN IASN IASN IASN ILYS ILYS ILYS ILYS ILYS ILYS ILYS ILYS ILYS IALA IALA IALA IALA IALA IPR0 IPRO IPRO IPRO IPRO IPRO IPRO ILEU ILEU ILEU ILEU ILEU I

222222232323232323232324242424242424242525252525252525252626262626272727272727272828282828

45.09549.18250.20849.20450.50250.31849.34448.55449.39451.17752.39150.33750.86849.69748.61547.43649.05851.78352.76951.38452.01151.23650.57349.29848.76547.51153.47954.35953.72755.09755.92055.15654.26156.23057.35756.40757.84358.35256.11556.80755.01254.58853.27252.57252.267

20.79016.71717.38415.37814.74013.22512.90713.75411.64715.23315.34815.51716.14716.73615.70816.02614.44517.29517.58618.01119.29220.07321.28721.71623.02123.38319.17719.46418.76818.63919.77318.72819.23618.15817.50218.12317.70716.97419.47920.46119.49620.74320.46121.74722.680

-15.993-14.144-14.054-14.279-14.456-14.479-15.579-15.992-16.047-15.731-15.826-16.746-17.953-18.743-18.883-19.024-18.938-17.596-18.259-16.541-16.317-15.261-15.901-15.180-15.758-15.112-15.941-16.732-14.680-14.190-14.793-12.659-12.003-12.104-12.756-10.655-10.383-11.621-10.015-10.226-9.237-8.605-7.864-7.428-8.604

84.9682.2382.9985.1087.6989.4691.9893.2892.8988.2088.0888.9889.4589.7690.7391.0390.9889.2289.6788.7788.1387.8388.0987.9687.4787.8687.8887.9387.2487.0386.8286.1786.4985.0084.7483.6884.5485.0582.7882.5981.3179.5379.2278.5679.42

IIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIII

NCONCCCONCONCCCONCONCCCCCNCONCCCONCCCCCONCCCC

CD2CONCACOCBSGNCACBCONCACONCACBOGCONCACBCGSDCECONCACBCG1CG2CONCACBCGCD2CE2

LEU ILEU ILEU ICYS ICYS ICYS ICYS ICYS ICYS IALA IALA IALA IALA IALA IGLY IGLY IGLY IGLY ISER ISER ISER ISER ISER ISER IMET IMET IMET IMET IMET IMET IMET IMET IVAL IVAL IVAL IVAL IVAL IVAL IVAL ITRP ITRP ITRP ITRP ITRP ITRP I

282828292929292929303030303031313131323232323232333333333333333334343434343434353535353535

51.23855.64855.96656.23357.06358.55859.39956.38755.32158.83360.14460.81961.08062.29860.48261.11260.34459.22060.98860.31759.38260.01359.51758.51959.99059.32360.38461.25960.79361.65258.58059.08457.29356.48955.26255.68454.53256.02956.05455.61855.10354.95856.27257.29758.343

21.48321.31920.77022.45123.31122.92723.72423.64825.11021.63821.24222.49220.54720.71819.71719.42820.18119.84521.23822.07323.06424.34221.25220.62821.25320.42019.55518.85217.13816.45221.24822.19520.87421.58822.18323.29621.10720.70019.47921.35520.60221.56722.14621.51722.460

-6.732-7.638-6.599-8.080-7.222-7.126-6.710-5.869-5.991-7.488-8.025-8.580-7.032-7.049-6.179-4.906-3.821-3.484-3.271-2.255-2.969-3.017-1.233-1.5530.0351.0431.7130.6860.4581.8742.0852.6642.2813.2702.5781.6261.8004.4504.3725.5486.6827.8628.2259.0279.190

78.5278.9778.2578.3778.8079.6481.1978.0279.5379.6179.8879.9179.6780.1179.2179.3978.9180.3177.0875.2776.7780.2373.5173.9571.5068.9669.8570.7273.7472.5166.8767.9664.1262.2262.0260.1058.2562.1161.4761.6862.6063.9866.8867.7068.28

IIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIII

CCONCCOCSNCCCONCCONCCOCONCCCSCCONCCCCCONCCCCC

CE3CD1NE1CZ2CZ3CH2CONCACBOGCONCACBCG2CG1CD1CONCACBCGOD1ND2CONCACBCGCD1CD2CONCACBOG1CG2CO

TRP ITRP ITRP ITRP ITRP ITRP ITRP ITRP ISER ISER ISER ISER ISER ISER IILE IILE IILE IILE IILE IILE IILE IILE IASN IASN IASN IASN IASN IASN IASN IASN ILEU ILEU ILEU ILEU ILEU ILEU ILEU ILEU ITHR ITHR ITHR ITHR ITHR ITHR ITHR I

353535353535353536363636363637373737373737373838383838383838393939393939393940404040404040

57.41356.73857.95759.46158.53159.56653.74252.84053.61752.27552.41452.74251.38351.83150.06949.13848.52549.64147.72646.65648.01547.84447.24946.11745.87246.01045.72746.42744.85344.31844.40143.19143.21644.41644.56744.33141.92440.88742.04840.90441.42240.75242.92640.08638.886

20.26023.44123.70022.13119.93020.87319.99420.65218.68018.09516.57116.23318.64019.02318.70519.28420.52721.48620.11821.15018.31617.24718.72317.91518.20016.92516.86615.86218.23719.33717.23017.40316.36916.55715.41517.84517.22516.76317.57417.44117.07417.87517.34518.73418.762

9.6147.9178.4669.94210.36110.5206.3565.8556.6096.5746.7028.0487.6898.7637.3888.3487.7037.2466.4616.1068.7358.1639.75710.19211.67512.46813.66011.7589.3879.4228.6137.8176.6915.7614.7534.9448.6628.2019.95610.85012.24113.21612.32810.91910.684

68.1966.9967.3669.1668.9169.2362.3762.1561.2061.8462.3165.8560.4560.1360.8762.7660.9860.5861.4763.2064.5564.4067.1969.1671.4874.5376.3076.8970.3870.9471.6773.2671.4270.7269.8768.5674.7675.6876.5078.4378.8980.3780.3078.7080.14

IIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIII

CCNCCCCONCCOCONCCCCCCONCCCONCONCCCCCCONCCOCCO

NCACBCONCACONCACBCGSDCECONCACBCGCD1CE1CD2CE2CZOHCONCACOCBSGNCACBCONCACBCO

ALA IALA IALA IALA IALA IGLY IGLY IGLY IGLY IMET IMET IMET IMET IMET IMET IMET IMET ITYR ITYR ITYR ITYR ITYR ITYR ITYR ITYR ITYR ITYR ITYR ITYR ICYS ICYS ICYS ICYS ICYS ICYS IALA IALA IALA IALA IALA IALA IALA IALA IALA IALA I

414141414142424242434343434343434344444444444444444444444445454545454546464646464747474747

40.77540.09739.37541.08342.29540.52241.38542.46043.56642.10943.06642.56042.55640.97341.01443.26444.34442.16442.29340.99640.00940.41139.50538.68737.77938.18337.29643.47944.37143.45444.56845.86346.95344.21242.72145.72046.89846.47547.57548.79246.74347.30446.18747.93748.926

19.82621.11521.19922.27622.10523.49124.64924.35924.88323.45123.06321.78621.88721.41222.48724.16624.36224.87825.97426.78526.17325.75725.13925.98025.37124.95224.30226.86927.13127.37028.19227.37927.85428.77129.79226.11925.27223.96624.97824.97624.67924.44823.96525.72425.704

11.30111.37612.72111.23811.22011.10110.9119.8629.8908.9347.9077.2355.7095.0023.5616.8656.3236.5545.6025.6044.6713.4032.5525.0714.2172.9632.1265.9675.1707.2167.6747.7677.4779.0468.9998.2238.3769.0517.0326.9046.0164.6903.7644.1313.410

77.6576.5177.9875.3976.8572.2667.3965.3463.6462.5861.8164.3167.1073.2970.9558.7859.6654.9450.8851.7351.6751.0851.6251.4252.7353.1354.4948.1545.2548.3949.3749.6248.3651.1556.4349.1547.9747.7747.4747.0845.7046.2944.9946.2546.92

IIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIII

NCCCONCCONCCCSCCONCCCCCCCCOCONCCOCSNCCCONCCCO

NCACBCGCD1CD2CONCACBCGCDOE1OE2CONCACBOGCONCACBCGCD1CD2CONCACBCG2CG1CD1CONCACBCGOD1ND2

LEU ILEU ILEU ILEU ILEU ILEU ILEU ILEU IGLU IGLU IGLU IGLU IGLU IGLU IGLU IGLU IGLU ISER ISER ISER ISER ISER ISER ILEU ILEU ILEU ILEU ILEU ILEU ILEU ILEU IILE IILE IILE IILE IILE IILE IILE IILE IASN IASN IASN IASN IASN IASN I

484848484848484849494949494949494950505050505051515151515151515252525252525252535353535353

47.29847.86346.89147.49447.72946.60649.22850.20449.25550.46750.13249.44350.46151.14350.58751.61752.77951.25552.36351.90952.79352.80253.96151.81252.11850.82150.53349.44251.76052.71253.18852.63753.12452.51953.29352.62752.04554.65255.26855.26556.72057.11156.76857.02956.161

26.86428.14929.25230.65731.07631.74028.36828.75928.12428.35228.09029.28330.37530.34131.23927.44227.65226.37125.49424.04723.17525.71225.55926.04126.26626.11924.66824.55623.95227.65827.99628.49129.85930.68830.42832.18132.52529.93130.95828.79828.76527.73228.26129.41327.379

4.4594.0624.4964.3812.9284.9984.7204.0936.0446.8228.2898.9469.16710.1818.3006.3886.7185.6625.2985.4934.7863.8473.4842.9971.5890.7930.401-0.665-0.1651.3580.2822.4132.2853.4194.7243.0981.7272.3412.0872.7302.8183.8765.2445.5786.056

45.8044.8343.5142.2939.2841.4545.5745.6246.2047.2549.5751.3254.8858.3553.8548.2349.0648.3848.7749.0249.2148.1848.7347.1047.8946.6949.0450.2146.4348.6348.4149.3050.6149.7949.2148.5945.0451.0553.8351.0251.3347.6047.6546.8745.54

IIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIII

NCCCCCCONCCCCOOCONCCOCONCCCCCCONCCCCCCONCCCON

CONCACBCG1CG2CONCACBOGCONCACONCACOCBSGNCACBOGCONCACBCONCACBCG2CG1CD1CON

ASN IASN IVAL IVAL IVAL IVAL IVAL IVAL IVAL ISER ISER ISER ISER ISER ISER IGLY IGLY IGLY IGLY ICYS ICYS ICYS ICYS ICYS ICYS ISER ISER ISER ISER ISER ISER IALA IALA IALA IALA IALA IILE IILE IILE IILE IILE IILE IILE IILE IGLU I

535354545454545454555555555555565656565757575757575858585858585959595959606060606060606061

57.36058.57356.53357.10055.99756.54455.48457.69657.02559.01659.70161.06061.38459.90260.19259.68360.02059.27159.85057.94257.16655.80355.02856.99956.07155.72654.57854.95855.07353.31952.26653.45552.32652.86851.36650.18751.90651.03351.74351.25753.25653.94850.60249.86751.112

28.40728.41828.02027.65327.03126.69025.76528.86629.84628.79029.91830.07631.46329.71728.63130.81430.81429.74228.97529.68728.78829.40229.82627.49826.19229.76230.53831.23630.27029.68730.16928.37527.48426.10127.38427.09127.59827.51426.74425.28426.74127.89028.88729.01829.943

1.4751.3130.484-0.810-1.665-3.050-1.006-1.528-1.826-1.772-2.390-1.702-1.600-3.895-4.378-4.647-6.068-6.869-7.626-6.661-7.503-7.865-7.003-6.693-7.524-9.162-9.626-10.936-11.982-9.825-10.222-9.562-9.813-10.175-8.621-8.765-7.403-6.233-5.117-5.096-5.334-4.598-5.721-4.752-6.377

53.5355.0355.9557.7756.6253.9657.4259.2160.1560.6463.2562.7963.7763.8764.1465.4467.0067.9268.1568.5468.8167.6166.7670.7675.7765.8865.2665.5666.5564.1563.5062.8262.0961.0962.0361.3860.6061.2962.0261.6362.9265.7760.9260.6760.36

IIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIII

CONCCCCCONCCOCONCCONCCOCSNCCOCONCCCONCCCCCCON

CACBCGCDOE1OE2CONCACBCGCDCENZCONCACBOG1CG2CONCACBCGCDOE1NE2CONCACBCGCDNECZNH1NH2CON

GLU IGLU IGLU IGLU IGLU IGLU IGLU IGLU ILYS ILYS ILYS ILYS ILYS ILYS ILYS ILYS ILYS ITHR ITHR ITHR ITHR ITHR ITHR ITHR IGLN IGLN IGLN IGLN IGLN IGLN IGLN IGLN IGLN IARG IARG IARG IARG IARG IARG IARG IARG IARG IARG IARG IMET I

616161616161616162626262626262626263636363636363646464646464646464656565656565656565656566

50.75251.39752.37352.33451.63753.01849.23148.67748.55047.09646.57045.07044.59143.07842.63046.43145.44246.98546.45247.19646.85346.78246.62545.75047.82848.06449.44450.57751.90152.05652.89147.00446.49246.70245.77145.89247.11647.19947.73249.03249.77149.59544.32943.52643.996

31.27432.31833.21734.61235.45634.84831.46031.95431.06731.20430.75231.01630.84830.62130.83630.38930.79029.18528.35527.02126.29926.19229.03729.03029.60130.38031.02630.03830.74631.71730.21131.46931.72432.14733.26334.09535.01335.97737.27337.53536.67138.62432.80233.47731.620

-5.910-6.823-6.060-6.640-6.093-7.635-5.849-4.877-6.943-6.956-8.319-8.470-9.912-10.004-11.379-5.842-5.243-5.602-4.525-4.530-5.714-3.310-3.168-2.312-2.971-1.766-1.889-1.627-1.780-2.504-1.040-1.597-0.516-2.718-2.639-3.919-3.869-5.060-4.625-4.870-5.541-4.337-2.402-1.771-2.951

59.6962.5368.6471.6672.0474.3357.4356.7355.2454.1154.4255.7057.8458.7659.4651.7051.2149.6849.4049.6649.0248.3249.9449.1650.0049.1849.5650.1051.3053.2447.6049.3050.2349.3749.5252.3755.4358.2061.2660.3762.1359.8447.2346.8745.98

IIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIII

CCCCOOCONCCCCCNCONCCOCCONCCCCONCONCCCCNCNNCON

CACBCGSDCECONCACBCGCD1CD2CONCACBOGCONCACONCACBCGCD1CD2CE1CE2CZCONCACOCBSGNCDCA

MET IMET IMET IMET IMET IMET IMET ILEU ILEU ILEU ILEU ILEU ILEU ILEU ILEU ISER ISER ISER ISER ISER ISER IGLY IGLY IGLY IGLY IPHE IPHE IPHE IPHE IPHE IPHE IPHE IPHE IPHE IPHE IPHE ICYS ICYS ICYS ICYS ICYS ICYS IPRO IPRO IPRO I

666666666666666767676767676767686868686868696969697070707070707070707070717171717171727272

42.65042.40242.42942.13240.41942.44341.38943.48543.40244.65844.68746.05243.67043.27142.55044.03443.91344.80146.15942.46041.99441.74740.33539.52638.60039.88039.17839.42338.52139.04337.23638.28636.48337.00639.67438.99540.92941.53442.19443.41842.57243.27441.35939.90241.820

31.10529.95330.42029.07629.46330.64930.82930.00929.63028.83827.46426.78526.49130.86030.87531.91233.15534.20633.76533.63234.27133.32233.67532.98933.54831.71630.97529.48128.95828.71828.54228.03527.85727.59631.37131.21831.85832.25133.61733.76331.18831.43934.67134.65736.017

-2.732-3.705-5.162-6.318-6.708-1.284-0.688-0.7230.6831.0460.3760.4900.9741.5832.5721.2311.9811.3141.3512.0082.9420.9090.8381.9422.5152.2063.2493.0221.9390.6742.253-0.2691.3020.0414.6445.6514.6795.9525.8445.8156.3207.9675.7475.8995.495

45.2246.6448.5452.1251.7943.9541.5042.0042.2242.5744.3541.1842.2541.4239.8542.6743.9843.6946.4544.5944.5545.2246.2548.0848.2448.0148.5549.3749.7947.8150.1147.1249.1747.0549.5949.4350.9851.3449.6648.0752.2556.3849.5648.3649.81

IIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIII

CCCSCCONCCCCCCONCCOCONCCONCCCCCCCCCONCCOCSNCC

CBCGCONCACBCGCD2ND1CE1NE2CONCACBCGCDCENZCONCACBCG1CG2CONCACBOGCONCACBCONCACO

PRO IPRO IPRO IPRO IHIS IHIS IHIS IHIS IHIS IHIS IHIS IHIS IHIS IHIS ILYS ILYS ILYS ILYS ILYS ILYS ILYS ILYS ILYS IVAL IVAL IVAL IVAL IVAL IVAL IVAL ISER ISER ISER ISER ISER ISER IALA IALA IALA IALA IALA IGLY IGLY IGLY IGLY I

727272727373737373737373737374747474747474747475757575757575767676767676777777777778787878

40.60639.37242.48343.48941.83442.36641.18940.87740.02941.44340.95240.10343.10042.52544.41945.10246.43947.27848.76149.43949.38044.23544.16643.48742.97641.59141.65841.25843.83543.35945.12745.96347.38347.40445.69245.81045.28945.87445.18045.85344.83047.06147.15248.52548.765

36.85336.15236.61237.30136.34736.83437.29238.72839.23839.76540.87640.59035.73534.73835.90834.98135.61534.68735.05934.79135.99434.70735.50433.58132.99732.40831.35731.68431.83830.78631.97331.36331.50830.93132.23233.45231.65030.45630.23329.18628.56028.80427.66227.00826.088

5.1125.6706.7386.6857.8859.14810.0039.7058.71810.3699.7878.7969.89010.31010.02210.90011.31612.19912.19513.54214.37212.13513.06512.07113.30813.14512.04014.44713.73414.12913.52314.53113.98412.65315.77515.71216.94017.55718.90316.72916.48116.29915.39715.45816.231

48.7348.3250.3149.6052.6354.7553.2251.2149.7850.0752.2050.8857.3656.8962.0366.8466.7967.6267.4267.4166.8370.7172.1376.5380.6080.9980.4181.8083.1084.0186.1888.8389.6189.5190.5991.5692.0592.6492.8492.8392.9593.0092.7392.5893.01

IIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIII

CCCONCCCCNCNCONCCCCCNCONCCCCCONCCOCONCCCONCCO

NCACBCONCACBCGOD1OD2CONCACBOG1CG2CONCACBCGCDCENZCONCACBCG2CG1CD1CONCACBCGCDOE1OE2C

ALA IALA IALA IALA IALA IASP IASP IASP IASP IASP IASP IASP IASP ITHR ITHR ITHR ITHR ITHR ITHR ITHR ILYS ILYS ILYS ILYS ILYS ILYS ILYS ILYS ILYS IILE IILE IILE IILE IILE IILE IILE IILE IGLU IGLU IGLU IGLU IGLU IGLU IGLU IGLU I

868686868687878787878787878888888888888889898989898989898990909090909090909191919191919191

52.37153.58453.41654.82055.78654.77955.90756.61656.63855.66657.61656.88858.07456.34257.18856.65255.39056.45857.20256.32258.27258.38959.76859.80460.75760.34061.03158.21459.08457.01756.74155.31655.21854.33252.89256.88356.94756.98057.01657.28058.64658.89260.02757.93555.712

15.40814.62113.77415.51315.40716.39317.29117.50518.99119.46419.65516.72016.55016.38215.83514.45214.60213.60816.73917.56116.59117.40918.07019.33220.39121.81522.77616.57615.82316.70515.96015.41214.39516.54816.04916.84418.06416.26317.10816.21815.53914.78714.39714.58917.891

13.59313.40912.14713.27814.02112.26012.04013.37713.70214.29213.36711.01411.2679.8318.7778.4057.7539.6687.5437.3246.7405.5405.5456.4105.8536.2355.3784.2683.8533.6662.4432.5313.6832.8242.9581.2021.280-0.006-1.181-2.392-2.323-3.605-3.857-4.343-1.355

92.3691.8291.5790.7290.7589.2986.8387.7589.1289.7788.9584.2883.9480.9077.3677.2577.9077.0174.9175.0472.5770.3671.2872.0472.0172.2173.0968.2069.4163.9861.1061.0260.6260.1858.7259.3160.1957.2756.0155.9459.7961.2764.1162.3354.80

IIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIII

NCCCONCCCOOCONCCOCCONCCCCCNCONCCCCCCONCCCCOOC

ONCACBCG1CG2CONCACBCONCACBCGCDOE1NE2CONCACBCGCD1CD2CE1CE2CZCONCACBCG1CG2CONCACBCGCD

GLU IVAL IVAL IVAL IVAL IVAL IVAL IVAL IALA IALA IALA IALA IALA IGLN IGLN IGLN IGLN IGLN IGLN IGLN IGLN IGLN IPHE IPHE IPHE IPHE IPHE IPHE IPHE IPHE IPHE IPHE IPHE IVAL IVAL IVAL IVAL IVAL IVAL IVAL ILYS ILYS ILYS ILYS ILYS I

919292929292929293939393939494949494949494949595959595959595959595969696969696969797979797

54.64755.74954.57854.97453.78055.64653.57052.36554.04853.15853.93752.32251.15952.94852.22253.24452.53952.07352.80250.80551.35450.27251.80550.92751.68850.93651.11849.93150.44849.27149.54449.68748.53449.84348.73049.09947.85549.69647.82546.51748.44947.57448.49347.94649.050

17.52419.00019.82121.12221.94521.99919.08819.03918.41717.50516.57816.60316.41715.93415.01314.21813.17311.93211.46111.50615.74115.25816.92817.77419.00719.91219.79220.75220.56021.52421.46118.13417.99318.54719.09619.85620.21521.21017.93918.04416.86315.67914.58413.34112.597

-0.873-2.106-2.225-2.945-3.400-1.985-3.112-2.775-4.204-4.939-5.759-4.072-4.285-3.132-2.307-1.468-0.468-1.233-1.968-1.078-1.330-0.945-0.8960.0550.4441.5082.7771.1143.8102.1093.476-0.632-0.083-1.894-2.577-3.820-4.467-3.547-2.988-3.077-3.353-3.793-4.189-4.887-6.011

55.5353.3652.8653.8954.8653.8952.0749.5450.8251.2951.5051.7852.0251.8251.4351.3351.1753.1353.0152.9250.6751.6948.9646.8144.7645.4545.8745.9445.0845.2144.1645.9145.2145.2446.3645.7947.0844.2847.3447.2149.0951.5554.1760.4062.67

IIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIII

ONCCCCCONCCCONCCCCONCONCCCCCCCCCONCCCCCONCCCC

CENZCONCACBCGOD1OD2CONCACBCGCD1CD2CONCACBCGCD1CD2CONCACBCGCD1CD2CONCACBCGCD2ND1CE1NE2C

LYS ILYS ILYS ILYS IASP IASP IASP IASP IASP IASP IASP IASP ILEU ILEU ILEU ILEU ILEU ILEU ILEU ILEU ILEU ILEU ILEU ILEU ILEU ILEU ILEU ILEU ILEU ILEU ILEU ILEU ILEU ILEU ILEU ILEU IHIS IHIS IHIS IHIS IHIS IHIS IHIS IHIS IHIS I

9797979798989898989898989999999999999999100100100100100100100100101101101101101101101101102102102102102102102102102

49.06850.34346.71745.44747.32146.50147.33348.37449.30848.38245.44944.35245.77444.84045.44344.82945.24543.58643.61142.46843.85142.81743.59142.66941.71843.36941.89040.62042.44141.53242.30442.85143.90641.69640.59639.28841.15040.32041.19440.43440.06140.12239.38039.37339.281

13.41013.64615.25415.00015.20314.77214.61313.44013.48912.50215.88315.57517.19818.25119.59720.83322.15420.93418.03418.23017.76017.75417.64417.41118.51917.19916.64616.75415.49814.41613.11912.53711.50411.86214.74714.48115.48615.78916.40616.77417.96315.87316.45617.74116.813

-7.468-8.370-2.591-2.673-1.392-0.2161.0150.9801.9210.1190.0890.548-0.1060.3390.0230.627-0.0151.092-0.533-0.102-1.794-2.807-4.248-5.353-5.349-6.753-2.616-2.540-2.233-1.832-1.634-2.978-2.808-3.903-0.682-0.6280.2141.3342.4303.6414.1074.6105.5185.2600.903

66.0566.5751.1650.7652.0952.2054.8059.1961.3861.5851.3951.7147.7447.4545.4944.8943.6043.9846.9347.4645.7644.5343.5543.6442.8640.1144.8645.2445.3646.0145.9245.9146.5143.0746.6648.0046.6948.3151.0351.8253.2353.1254.5056.0648.41

IIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIII

CNCONCCCOOCONCCCCCCONCCCCCCONCCCCCCONCCCCNCNC

ONCACBCGCD1CD2CONCACBCGCDCENZCONCACBCGCDCENZCONCACBCGCD1CD2CONCACBCGCD1CD2CE1CE2CZC

HIS ILEU ILEU ILEU ILEU ILEU ILEU ILEU ILEU ILYS ILYS ILYS ILYS ILYS ILYS ILYS ILYS ILYS ILYS ILYS ILYS ILYS ILYS ILYS ILYS ILYS ILYS ILEU ILEU ILEU ILEU ILEU ILEU ILEU ILEU IPHE IPHE IPHE IPHE IPHE IPHE IPHE IPHE IPHE IPHE I

102103103103103103103103103104104104104104104104104104105105105105105105105105105106106106106106106106106107107107107107107107107107107

38.10239.72438.67839.29240.35441.04439.73337.58536.46137.93736.86737.40238.30638.59139.24839.30635.92534.70636.45435.54736.26335.47436.34436.79937.72234.65833.42635.16134.24635.01636.15836.73735.58133.20632.04933.57632.58133.22932.37332.04031.78631.22730.98230.72631.505

16.80617.76318.70919.86920.78821.80921.56418.09518.43217.15416.49015.54916.28415.25015.98515.20415.73715.59615.18514.55713.77113.49313.03811.58211.20015.48015.19316.67317.68118.90918.68920.08718.00118.13018.32818.25618.73118.77619.34020.66618.48721.17718.92920.23517.720

1.3430.094-0.307-1.094-0.467-1.3410.838-1.176-1.074-2.005-2.802-3.797-4.777-5.921-7.140-8.323-1.861-2.147-0.8190.1421.1482.4863.6153.3644.6010.8790.8991.3471.9252.3673.3453.6804.4460.9441.266-0.333-1.318-2.639-3.734-3.816-4.567-4.966-5.609-5.871-1.389

46.8748.4749.5648.4849.0949.0045.1050.1049.9550.8550.8649.1248.4047.5748.8847.9650.9250.7152.0854.2556.5560.3363.2266.1671.2754.6654.5955.3155.1955.6356.6056.0456.8055.2553.5155.9256.0453.8952.3952.1352.0953.2152.5451.7857.69

IIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIII

ONCCCCCCONCCCCCNCONCCCCCNCONCCCCCCONCCCCCCCCC

ONCACBCGCDNECZNH1NH2CONCACBCGCDOE1OE2CONCACONCACBCGCDNECZNH1NH2CONCACBCGCD1CD2CE1CE2CZ

PHE IARG IARG IARG IARG IARG IARG IARG IARG IARG IARG IARG IGLU IGLU IGLU I6LU IGLU IGLU IGLU IGLU IGLU IGLY IGLY IGLY IGLY IARG IARG IARG IARG IARG IARG IARG IARG IARG IARG IARG IPHE IPHE IPHE IPHE IPHE IPHE IPHE IPHE IPHE I

107108108108108108108108108108108108109109109109109109109109109110110110110111111111111111111111111111111111112112112112112112112112112

30.30931.89130.88131.60830.75431.66732.69534.06934.75734.78429.99428.81930.52429.67530.55231.15632.32932.63732.93728.90528.15629.03128.28528.74927.92930.06530.80231.69530.97731.33132.50533.53433.45834.64131.65032.82230.99631.70130.68230.16730.57629.32630.14728.90129.311

17.98616.49015.51114.19912.87311.58411.00311.18211.98910.51915.43915.16815.64615.62915.41314.03213.68012.42814.56316.94817.04717.96719.19020.23220.90020.28021.11420.20218.91918.50017.62117.96619.05017.21922.16521.97123.29724.36525.13824.26124.49023.20123.64322.35722.571

-1.382-1.534-1.665-2.008-2.025-2.519-1.599-1.590-2.451-0.653-0.290-0.3580.9262.1133.3343.3484.3114.2695.0452.2763.1451.4421.7162.8113.4733.0363.9764.8165.2336.6646.6657.4618.2147.4703.2532.9552.9312.2301.3920.290-1.0180.586-2.030-0.435-1.744

57.1860.0363.9665.1567.1668.8570.0070.8170.7770.3466.0966.7768.3170.4872.4174.9677.1577.9178.4571.2672.4271.4772.7873.7073.7374.7675.9276.3477.7079.6080.8081.1980.9881.5676.6975.6778.0479.3679.3078.6778.2678.4677.9479.0678.48

IIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIII

ONCCCCNCNNCONCCCCOOCONCCONCCCCNCNNCONCCCCCCCC

COOXTCBCGCONCDCANCDCACBCGCONCACBCG1CG2CONCACB0G1CG2CONCACBCGOD1ND2CONCACBCGCD1CD2

PHE IPHE IPHE IPRO RPRO RPRO RPRO RPRO RPRO RPRO RPRO RPRO RPRO RPRO RPRO RPRO RPRO RVAL RVAL RVAL RVAL RVAL RVAL RVAL RTHR RTHR RTHR RTHR RTHR RTHR RTHR RASN RASN RASN RASN RASN RASN RASN RASN RLEU RLEU RLEU RLEU RLEU RLEU R

112112112333333333333333434343434343435353535353535363636363636363737373737373737383838383838

32.40232.66532.72977.29677.63475.60074.66176.84376.86276.93575.50876.39374.28774.52975.70273.22273.08272.41371.46670.05770.11969.43271.75672.15571.61871.68272.11073.53471.55270.52769.35271.06870.68969.95069.67769.06170.26970.30271.12868.98868.26168.99967.99967.01668.648

25.31426.47024.9586.5087.0717.4488.2228.8838.4677.6886.3675.2276.1915.0744.2415.7476.1664.8514.3194.4675.2363.0952.8612.0892.5451.1910.9380.821-0.4390.3420.681-0.838-1.982-3.094-2.566-1.530-3.216-1.704-1.673-1.564-1.183-0.2410.3281.3371.016

3.2052.9054.32912.09113.46610.48910.61612.02113.41511.1889.6999.4798.9657.9558.4339.91211.0489.40310.3089.7388.4199.49810.5819.68411.85812.15913.62613.58614.04111.73811.80611.40210.49111.24512.59212.69313.5949.0428.1348.9427.6916.7195.6706.2814.469

79.8979.5581.92109.80109.72109.45109.75109.73110.08109.68108.90108.56108.17108.27108.37107.50107.84106.22105.21105.03104.78105.97104.36104.20103.37101.83101.92102.34101.87100.49100.3098.7797.0297.9198.5999.0498.7595.5995.9792.7189.8889.1888.7187.7588.12

IIIRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRR

COOCCCONCCNCCCCCONCCCCCONCCOCCONCCCONCONCCCCC

CONCACBOGCONCACBCG1CG2CONCACBOGCONCACBCG1CG2CONCACBCGCDOE1OE2CONCACBCGOD1ND2CO

LEU RLEU RSER RSER RSER RSER RSER RSER RVAL RVAL RVAL RVAL RVAL RVAL RVAL RSER RSER RSER RSER RSER RSER RVAL RVAL RVAL RVAL RVAL RVAL RVAL RGLU RGLU RGLU RGLU RGLU RGLU RGLU RGLU RGLU RASN RASN RASN RASN RASN RASN RASN RASN R

383839393939393940404040404040414141414141424242424242424343434343434343434444444444444444

67.58868.10166.42465.72265.44664.39964.39163.91763.82062.58662.95163.53661.71361.59661.95860.29959.25758.69557.87158.13958.13357.18856.04456.34555.04057.23954.75754.45654.00952.69052.36453.53553.10552.04053.84951.62851.88650.40449.32949.10548.59848.99847.67649.68150.000

-2.346-2.866-2.757-3.927-4.868-4.315-3.565-2.438-4.574-4.334-4.112-5.391-3.716-5.496-6.656-5.134-6.146-6.038-7.172-5.936-4.987-6.889-6.727-7.421-7.685-6.540-7.294-8.476-6.404-6.791-5.955-5.884-5.130-4.530-5.147-6.569-6.038-7.036-6.870-5.371-4.762-3.674-5.493-7.528-8.706

6.9455.9437.4626.9338.1048.9066.2466.3015.5514.8083.3402.7432.5574.9365.0784.9135.0566.4766.7444.0323.2604.0113.1221.7931.0420.9403.7253.6344.4014.8796.1187.1018.3398.3209.3193.8022.7304.1023.1332.9304.2114.6154.8611.7981.712

88.3188.2386.4385.0484.8084.6883.8383.0482.7581.4881.5581.2281.1780.9781.0080.3979.0379.2580.2178.2078.1277.0275.7575.6374.2375.0075.2576.2674.6974.3374.9176.6778.1278.6678.9173.2872.0173.8773.9174.1073.6673.7172.6574.2574.82

RRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRR

CONCCOCONCCCCCONCCOCONCCCCCONCCCCOOCONCCCONCO

NCACBCGCD1CD2CONCACBSGCONCACBOG1CG2CONCACBCG1CG2CONCACBCG2CG1CD1CONCACBCGCD2CE2CE3CD1NE1

LEU RLEU RLEU RLEU RLEU RLEU RLEU RLEU RCYS RCYS RCYS RCYS RCYS RCYS RTHR RTHR RTHR RTHR RTHR RTHR RTHR RVAL RVAL RVAL RVAL RVAL RVAL RVAL RILE RILE RILE RILE RILE RILE RILE RILE RTRP RTRP RTRP RTRP RTRP RTRP RTRP RTRP RTRP R

454545454545454546464646464647474747474747484848484848484949494949494949505050505050505050

49.57749.89448.63048.03446.99249.08651.02051.86750.98452.00451.35450.63352.62953.63851.96452.48951.52950.20351.91853.88654.06354.90356.28057.12856.46058.51056.83156.75557.36657.81757.14557.52055.62154.89559.34059.98859.88061.30161.92362.45161.78662.70160.51563.74363.958

-6.724-7.249-7.177-8.558-8.520-9.581-6.452-6.982-5.124-4.267-3.448-4.496-3.335-2.680-3.262-2.429-2.523-2.240-1.501-2.880-3.827-2.190-2.524-2.444-1.520-1.913-1.570-0.354-2.165-1.346-1.876-0.994-1.837-2.073-1.378-2.402-0.181-0.0801.0070.4310.431-0.0930.815-0.102-0.433

0.725-0.598-1.455-1.742-2.860-2.172-1.261-1.968-1.041-1.633-2.750-4.034-0.593-0.8210.5751.6502.8362.3873.9092.0782.8341.5261.8740.603-0.4150.9302.9392.8284.0205.1416.4077.6116.2537.5785.3035.1285.6045.9155.0353.7782.4931.5462.0773.5622.260

74.5273.9375.6077.3176.9577.3873.8573.5573.0972.7373.7979.4871.5771.9570.1569.2169.2569.2468.4968.9469.5368.0568.5867.2469.1167.3668.6269.2569.0268.8468.7868.3568.1770.5868.4669.7767.5767.7665.2763.0962.6662.2461.2763.4161.66

RRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRR

NCCCCCCONCCSCONCCOCCONCCCCCONCCCCCCONCCCCCCCN

CZ2CZ3CH2CONCACBOG1CG2CONCACBCGCD2CE2CE3CD1NE1CZ2CZ3CH2CONCACBCGOD1ND2CONCDCACBCGCONCDCACB

TRP RTRP RTRP RTRP RTRP RTHR RTHR RTHR RTHR RTHR RTHR RTHR RTRP RTRP RTRP RTRP RTRP RTRP RTRP RTRP RTRP RTRP RTRP RTRP RTRP RTRP RASN RASN RASN RASN RASN RASN RASN RASN RPRO RPRO RPRO RPRO RPRO RPRO RPRO RPRO RPRO RPRO RPRO R

505050505051515151515151525252525252525252525252525253535353535353535454545454545455555555

62.32060.13361.04561.51460.90162.39562.71762.09962.46560.57164.22164.99564.63566.05266.66866.11465.06764.98964.19266.62466.00964.05263.25563.18366.29365.38467.56367.82968.54567.52666.72167.49368.65769.35368.51367.55869.36769.02267.67070.83771.22571.65971.35873.06073.751

-0.2270.6780.1580.2801.187-0.499-0.217-1.313-2.591-1.190-0.181-0.8520.6830.7951.7243.0933.6755.0513.1554.1415.3315.8643.9675.3291.3451.5311.5682.1051.0400.0380.304-1.1033.3713.6614.1614.0315.3065.9005.3364.8753.7865.7677.1245.4746.798

0.2200.754-0.1827.3837.9338.0309.41410.2839.76110.2719.6128.93710.54310.8149.7589.8759.0579.3928.10610.67410.4318.7727.4887.82812.20813.00712.52313.83814.66015.12716.01414.42313.78012.81414.85415.93915.06816.43316.85715.02015.40814.47114.07614.19613.888

62.5961.7063.1469.6071.1871.7073.5572.5672.8172.2275.3775.3877.4179.2679.7580.8981.5681.9981.2981.4581.2181.9681.0881.2680.4279.4382.9585.2686.5788.4189.4688.4785.9984.9187.4687.1388.9688.5187.8191.1691.9592.7792.9094.3893.93

RRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRR

CCCCONCCOCCONCCCCCCCNCCCCONCCCONCONCCCCCONCCC

CGCONCACOCBSGNCACBOGCONCACBCGCD1CD2CONCACBCGCD2CE2CE3CD1NE1CZ2CZ3CH2CONCACBCGCD1CE1CD2CE2

PRO RPRO RPRO RCYS RCYS RCYS RCYS RCYS RCYS RSER RSER RSER RSER RSER RSER RLEU RLEU RLEU RLEU RLEU RLEU RLEU RLEU RTRP RTRP RTRP RTRP RTRP RTRP RTRP RTRP RTRP RTRP RTRP RTRP RTRP RTRP RTYR RTYR RTYR RTYR RTYR RTYR RTYR RTYR R

555555626262626262636363636363646464646464646465656565656565656565656565656666666666666666

72.73973.76173.82371.15170.42069.05768.95171.26872.17268.00166.74965.73765.28266.93267.01466.99567.20767.50268.99269.87769.56265.97464.83366.23765.27164.79363.70963.88662.59665.00862.32161.59962.46364.87863.59665.91867.01065.21965.71165.25565.67864.72165.10867.03467.423

7.9244.7745.28815.10815.51014.81613.59715.15416.58115.64315.21416.34416.39414.88315.75113.57213.15511.64611.27512.25811.21713.41213.27313.85413.62714.95615.53216.34416.73516.78915.44716.12317.57117.61818.02112.80713.08611.73510.8969.4619.0528.8148.4508.9318.576

14.11215.36516.47419.86018.66418.58118.58117.43716.78318.51417.86618.00319.35216.37915.52416.07114.68914.68614.69513.92216.10513.82214.24312.57811.50910.92411.74212.91913.35413.60411.50612.43814.45414.70415.12410.4019.92710.0138.9429.19810.57111.55312.83110.88712.169

93.3296.1996.5197.9899.92100.12100.53100.74104.16100.26100.59100.76100.96100.67101.08100.0799.2299.84100.27100.3999.9898.4098.8797.0395.8396.9697.9198.9199.1599.8598.1498.5599.73100.22100.0393.8993.8691.5689.7489.5889.5389.3889.1489.3489.67

RRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRR

CCONCCOCSNCCOCONCCCCCCONCCCCCCCNCCCCONCCCCCCC

CZOHCONCACBCGCD1CD2CE1CE2CZCONCACBOGCONCACBCGCD2ND1CE1NE2CONCACBCGCD1CD2CE1CE2CZCONCAC

TYR RTYR RTYR RTYR RPHE RPHE RPHE RPHE RPHE RPHE RPHE RPHE RPHE RPHE RPHE RSER RSER RSER RSER RSER RSER RHIS RHIS RHIS RHIS RHIS RHIS RHIS RHIS RHIS RHIS RPHE RPHE RPHE RPHE RPHE RPHE RPHE RPHE RPHE RPHE RPHE RGLY RGLY RGLY R

666666666767676767676767676767686868686868696969696969696969697070707070707070707070717171

66.46566.84365.21164.03966.16865.77366.75367.09268.42566.08968.75666.42667.76065.81066.80464.67764.63263.90562.50363.98363.12964.44563.82864.39265.90266.78766.61067.88368.01964.01264.85063.15463.22262.32360.96560.56860.04559.23758.71058.30064.65465.22465.23766.67267.219

8.3438.00911.37811.67311.52611.89212.94913.91914.18514.64315.19715.66015.94510.6609.95910.3899.1728.0978.3809.34110.1818.4818.4619.6199.6289.5639.97410.1309.8907.1216.2946.9105.6485.7375.2075.2034.9494.9924.7384.7715.3104.3136.1626.0587.024

13.13914.4247.5777.3696.6445.2914.7795.8726.1506.4927.0377.3817.6534.3734.2983.6912.8833.6863.6821.4911.2650.525-0.821-1.656-1.623-2.709-0.520-0.934-2.239-1.574-1.242-2.611-3.369-4.605-4.259-2.929-5.264-2.605-4.930-3.603-3.771-3.375-4.615-4.768-5.802

89.5188.9388.1387.4487.1786.5387.7089.8790.9190.8490.9791.5590.8485.6785.4384.8584.4083.5581.9284.9684.4086.0287.6686.8587.4787.5887.2587.2387.4788.7088.9390.7892.9293.7195.1795.7496.2397.2996.9097.3794.2695.6494.5895.5195.90

RRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRR

COCONCCCCCCCCCONCCOCONCCCCNCNCONCCCCCCCCCONCC

ONCACBCGOD1OD2CONCACBCGCDCENZCONCACBCGCDOE1NE2CONCACBCGOD1OD2CONCACBCGCDCENZCON

GLY RASP RASP RASP RASP RASP RASP RASP RASP RLYS RLYS RLYS RLYS RLYS RLYS RLYS RLYS RLYS RGLN RGLN RGLN RGLN RGLN RGLN RGLN RGLN RGLN RASP RASP RASP RASP RASP RASP RASP RASP RLYS RLYS RLYS RLYS RLYS RLYS RLYS RLYS RLYS RLYS R

717272727272727272737373737373737373747474747474747474757575757575757576767676767676767677

68.39866.30466.68766.03164.67264.55863.78266.16966.09265.70865.46566.40467.50667.35768.03769.48864.00163.60063.22861.80561.60660.37760.64361.02660.35761.03361.21460.18559.33258.98157.50257.16456.72060.04160.00860.71561.44462.04663.13663.97163.14362.82860.52659.35061.096

7.1317.6828.4527.7827.2716.0678.0899.82110.6929.86811.08912.18212.42413.76313.77713.66811.47312.62110.39310.4419.3239.4798.7989.4047.48010.0929.03511.03910.7469.2619.0969.1418.86211.07810.33812.24712.68914.06514.00415.28516.51016.44912.78813.11112.452

-6.054-6.464-7.620-8.819-8.383-8.149-8.174-7.374-8.226-6.120-5.397-5.890-4.860-4.135-2.762-2.911-5.442-5.317-5.600-5.868-6.899-7.787-9.116-10.103-9.127-4.588-4.000-4.128-2.983-3.011-3.338-4.521-2.420-1.661-0.685-1.666-0.481-0.791-1.863-1.911-2.309-3.7350.7300.6371.902

96.5795.3994.7895.0395.2295.4095.6194.5494.6093.6692.2292.7593.4093.6893.8992.8290.8590.6989.3087.3488.2589.6791.5492.9591.9085.4885.7283.2380.1682.2184.2885.1484.6977.7676.1175.7273.2873.9473.6873.7774.5575.6172.2971.8870.63

RRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRR

ONCCCOOCONCCCCCNCONCCCCONCONCCCOOCONCCCCCNCON

CACBCGCDCENZCONCACBCG2CG1CD1CONCACBCONCDCACBCGCONCACBCONCACBOG1CG2CONCACBCGCD

LYS RLYS RLYS RLYS RLYS RLYS RLYS RLYS RILE RILE RILE RILE RILE RILE RILE RILE RALA RALA RALA RALA RALA RPRO RPRO RPRO RPRO RPRO RPRO RPRO RGLU RGLU RGLU RGLU RGLU RTHR RTHR RTHR RTHR RTHR RTHR RTHR RARG RARG RARG RARG RARG R

777777777777777778787878787878787979797979808080808080808181818181828282828282828383838383

60.33059.49658.86357.81456.87955.63761.24762.29760.83661.58662.19563.15663.00163.48960.69459.70161.06060.28159.10761.12962.18460.65059.41861.36560.67459.55661.36662.34460.19960.06058.70161.17161.60561.66862.63063.53162.72964.29861.89262.16460.89559.97858.78658.27257.196

12.58811.31911.25910.15310.3589.61612.79612.18713.72713.92015.31915.47515.52716.96913.74614.43512.75612.51211.60111.86011.28911.99712.63811.47812.01312.9639.9499.2989.3777.9297.5547.2137.6276.1215.2834.6073.8445.6694.2183.0284.7143.8353.5932.1541.978

3.1333.3334.7274.8466.0445.8304.3404.4795.2156.4506.4357.6275.1525.0067.6807.8698.5179.7249.36010.81910.57612.07012.49313.22814.48214.05213.25513.60112.91212.97212.38012.20311.13512.81212.10913.13614.03813.92911.29711.35710.5379.81910.74910.7029.629

69.4867.9267.2466.4066.7767.4069.9370.7869.9069.2370.1970.9070.7068.7468.6867.8868.9169.1668.8870.0869.5870.7370.7271.3771.3471.5271.7271.3771.9671.8971.7772.3372.1173.3974.3375.3876.1775.3373.7073.8273.7873.6674.6476.2278.40

RRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRR

CCCCCNCONCCCCCCONCCCONCCCCCONCCCONCCOCCONCCCC

NECZNH1NH2CONCACBCGCDNECZNH1NH2CONCACBOGCONCACBCG2CG1CD1CONCACBCGCDOE1OE2CONCACBCG1CG2

ARG RARG RARG RARG RARG RARG RARG RARG RARG RARG RARG RARG RARG RARG RARG RARG RARG RSER RSER RSER RSER RSER RSER RILE RILE RILE RILE RILE RILE RILE RILE RGLU RGLU RGLU RGLU RGLU RGLU RGLU RGLU RGLU RVAL RVAL RVAL RVAL RVAL R

838383838383848484848484848484848485858585858586868686868686868787878787878787878888888888

55.84754.93455.31253.63659.48859.06859.59859.03160.15459.60459.50758.60159.15460.46058.38058.15758.62556.83655.90654.73353.82855.39655.01655.43754.97256.19555.74457.00358.38454.14454.49652.97952.10850.67249.63248.27547.87747.64452.46751.99753.36753.87455.36956.02955.580

1.8992.8053.8542.4914.5255.6733.8054.3534.8235.4316.9607.4728.1608.3578.6213.3372.3763.5652.6762.4131.4993.2834.4442.4582.9333.3123.8794.3994.6031.8720.7012.3171.4111.9000.8761.3020.8412.1361.3982.2010.4640.4310.7460.4162.216

10.2019.7899.0749.8608.5428.5427.4116.1855.2623.9704.0433.0101.9961.9631.0085.4584.8635.5544.8815.8245.2043.5743.4932.5111.2150.379-0.9791.0940.4700.4880.413-0.019-0.758-0.574-1.028-0.5170.543-1.165-2.246-3.041-2.601-3.967-3.908-5.245-3.591

79.6680.9380.5480.5272.6872.8870.9069.8369.2368.6769.8967.6966.1663.9766.3269.5568.2669.1669.2468.2866.6769.3969.3370.4671.7971.5872.3171.3372.3772.3973.2273.4274.1073.4075.0775.3276.5174.9075.0675.3876.0977.6477.4877.3578.41

RRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRR

NCNNCONCCCCNCNNCONCCOCONCCCCCCONCCCCOOCONCCCC

CONCDCACBCGCONCACBCGCD1CD2CONCACBCGOD1ND2CONCACBCGCDOE1OE2CONCACBCONCACBCG2CG1CD1

VAL RVAL RPRO RPRO RPRO RPRO RPRO RPRO RPRO RLEU RLEU RLEU RLEU RLEU RLEU RLEU RLEU RASN RASN RASN RASN RASN RASN RASN RASN RGLU RGLU RGLU RGLU RGLU RGLU RGLU RGLU RGLU RARG RARG RARG RARG RARG RILE RILE RILE RILE RILE RILE R

888889898989898989909090909090909091919191919191919292929292929292929393939393949494949494

53.66753.77953.31053.00553.17752.60752.64254.52955.53954.53555.79855.66956.91558.05756.64956.14956.30556.24956.52555.77554.29453.85553.50458.02658.46458.82460.27260.62860.94560.92361.18060.64461.03860.48662.36463.20364.66562.93962.85662.76962.66461.25361.09460.20758.881

-0.949-1.982-0.9180.231-2.154-1.797-0.279-2.853-2.256-4.163-4.893-5.986-6.102-5.205-5.716-5.531-6.740-4.678-5.209-4.350-4.616-5.727-3.552-5.224-5.525-4.841-4.903-4.319-2.825-2.262-1.078-3.020-4.180-3.467-4.423-3.932-4.113-2.465-1.587-2.230-0.862-0.6520.802-0.907-1.413

-4.611-3.975-5.909-6.738-6.677-8.049-8.214-6.830-7.177-6.517-6.473-5.411-4.531-5.012-3.077-7.818-7.946-8.851-10.180-11.198-11.082-10.799-11.309-10.486-11.588-9.468-9.638-11.005-10.947-12.349-12.510-13.277-8.523-7.695-8.510-7.420-7.829-7.066-7.915-5.749-5.252-4.696-4.220-5.784-5.208

78.8379.0979.5879.4580.3679.9880.1080.6180.0582.1883.6183.4583.2682.8583.2584.4584.4585.7386.7987.2687.6488.2688.1487.6087.9188.4489.4491.0392.8294.7995.9195.7789.1689.1988.7088.3987.8287.7987.4087.2986.3786.4586.5986.3286.05

RRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRR

CONCCCCCONCCCCCCONCCCONCONCCCCOOCONCCCONCCCCC

CONCACOCBSGNCACBCGCD1CD2CONCACBCGCDOE1NE2CONCACBCG1CG2CONCACONCACBOGCONCACB

ILE RILE RCYS RCYS RCYS RCYS RCYS RCYS RLEU RLEU RLEU RLEU RLEU RLEU RLEU RLEU RGLN RGLN RGLN RGLN RGLN RGLN RGLN RGLN RGLN RVAL RVAL RVAL RVAL RVAL RVAL RVAL RGLY RGLY RGLY RGLY RSER RSER RSER RSER RSER RSER RGLN RGLN RGLN R

949495959595959596969696969696969797979797979797979898989898989899999999100100100100100100101101101

63.69563.83664.45765.50765.25264.95666.84067.23265.33665.17764.17463.81462.88565.03666.51367.32666.74667.96568.76868.84969.89570.19770.45067.64166.79668.32367.99167.54467.09866.38569.15770.31868.81269.83769.46468.41170.39670.12170.71071.80070.70971.78669.93670.42570.213

-0.604-1.3640.4920.7902.1123.1440.862-0.6922.0293.2192.8814.0963.7324.7663.6252.8024.9495.4486.2175.4716.1197.2985.2786.3637.2466.1046.8485.8546.6085.0267.6907.2988.9099.77610.2329.92410.95911.41510.3979.71512.79613.16213.59814.87915.904

-4.147-3.198-4.319-3.358-2.629-3.216-4.097-4.935-1.288-0.4600.6461.5042.6642.1300.1640.5610.2000.831-0.219-1.553-2.429-2.343-3.3242.0151.9453.1494.3595.4296.6814.9094.8804.8625.3315.8917.3057.8417.9319.28410.2659.6449.5509.08210.28810.7179.576

85.3884.6885.2185.6585.0986.1885.9487.8983.6882.8983.3284.2984.5884.5082.6382.8881.9681.6782.0083.0584.6685.5885.6681.3781.4680.6480.0679.3779.3278.5081.1681.2481.8882.6884.1083.6485.9087.8387.4788.3189.2589.4691.4893.6094.44

RRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRR

CONCCOCSNCCCCCCONCCCCONCONCCCCCONCCONCCOCONCC

CGCDOE1NE2CONCACOCBSGNCACBOGCONCACBCONCACBCONCACBCONCACBCONCACBCONCA

GLN RGLN RGLN RGLN RGLN RGLN RCYS RCYS RCYS RCYS RCYS RCYS RSER RSER RSER RSER RSER RSER RTHR RTHR RTHR RTHR RTHR RASN RASN RASN RASN RASN RPRO RPRO RPRO RPRO RPRO RSER RSER RSER RSER RSER RILE RILE RILE RILE RILE RLEU RLEU R

101101101101101101102102102102102102103103103103103103104104104104104105105105105105110110110110110111111111111111112112112112112113113

71.12771.26472.10470.36469.73068.84770.23169.46168.84769.46270.38071.77267.54866.59566.60665.53666.68867.64965.64265.03264.04366.02665.69967.27668.41969.65368.28867.45572.31472.84071.98673.97874.34474.75075.39976.87275.34175.75474.74675.16576.69274.41974.28173.92772.906

17.13217.81918.67617.41615.33814.68016.46817.28318.50919.20217.71816.58918.69619.62420.94020.92319.83120.35319.19519.70420.79520.14920.76919.78220.15119.32319.91619.20716.85515.91314.67215.07215.40314.11613.14313.51211.76411.46110.9229.5399.4518.8059.2997.6167.051

9.6928.3478.1257.42811.98412.54812.50213.41312.70311.91614.57214.79512.99512.35513.11514.06510.82110.24410.4399.1789.5298.0727.0767.9967.1157.5895.5675.0234.6365.6175.7705.0363.9165.9195.0744.9605.6686.8074.8404.7514.6993.6092.4863.9333.045

96.4698.3898.6899.0294.6494.6096.3298.1498.5398.75100.07103.2498.9599.3898.0896.6899.9399.9899.9699.76100.10100.47100.37100.2199.2797.8999.40100.19100.55100.45101.19101.27101.62100.1999.2997.7198.6998.5299.0499.5899.7099.23100.3297.6794.72

RRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRR

CCONCONCCOCSNCCOCONCCCONCCCONCCCONCCCONCCCONC

CBCGCD1CD2CONCACBCG1CG2CONCACBCGCDOE1OE2CONCACBCGCDCENZCONCACOCBSGNCACBCG2CG1CD1CO

LEU RLEU RLEU RLEU RLEU RLEU RVAL RVAL RVAL RVAL RVAL RVAL RVAL RGLU RGLU RGLU RGLU RGLU RGLU RGLU RGLU RGLU RLYS RLYS RLYS RLYS RLYS RLYS RLYS RLYS RLYS RCYS RCYS RCYS RCYS RCYS RCYS RILE RILE RILE RILE RILE RILE RILE RILE R

113113113113113113114114114114114114114115115115115115115115115115116116116116116116116116116117117117117117117118118118118118118118118

72.90972.33171.47671.41073.16074.05672.38072.51472.53472.37371.37471.34270.19971.71270.69571.31870.35071.06372.21770.45670.18570.90968.87468.33267.75767.43167.62468.55369.77967.24866.21467.53066.55065.65265.89767.30668.35564.54563.71462.48061.64661.62060.41463.30462.966

7.7919.2149.6169.3995.5605.1394.7363.2792.7063.8591.7502.6832.8222.1881.6711.5461.9421.8641.4582.2170.306-0.5140.096-1.235-1.337-2.785-3.735-4.910-4.808-1.545-0.904-2.544-2.801-3.988-4.726-3.088-1.705-4.039-5.216-5.009-3.807-6.260-6.308-5.663-4.886

1.6911.7770.5613.0132.8732.1543.6373.5254.9355.9155.1342.7463.1641.5540.650-0.742-1.858-3.189-3.213-4.1991.1101.6600.9161.1262.5342.9041.7182.0461.2550.0970.017-0.747-1.795-1.441-0.495-3.094-3.595-2.208-2.171-1.286-1.763-1.436-0.523-3.565-4.439

93.2392.8291.7091.4893.4593.2091.7390.6189.7489.4788.5490.7291.3890.1389.0089.8192.8594.8395.9896.1287.3087.7185.6784.1783.5883.4484.4585.5285.5983.7383.6783.5283.4282.8482.3284.0286.0282.7782.4881.3880.8280.7480.7283.5182.68

RRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRR

CCCCCONCCCCCONCCCCOOCONCCCCCNCONCCOCSNCCCCCCO

NCACBOGCONCDCACBCGCONCDCACBCGCONCACBCONCACONCACBCONCDCACBCGCONCACBCG

SER RSER RSER RSER RSER RSER RPRO RPRO RPRO RPRO RPRO RPRO RPRO RPRO RPRO RPRO RPRO RPRO RPRO RPRO RGLU RGLU RGLU RGLU RGLU RGLY RGLY RGLY RGLY RASP RASP RASP RASP RASP RPRO RPRO RPRO RPRO RPRO RPRO RPRO RGLU RGLU RGLU RGLU R

119119119119119119120120120120120120120121121121121121121121122122122122122123123123123124124124124124125125125125125125125126126126126

63.36163.15264.28865.35761.83461.29861.29261.79360.06159.83761.07860.19561.24659.05257.67959.03157.58556.73359.71060.23259.71260.46660.75459.75058.76560.29059.90360.09660.61259.74059.44259.96059.66359.29860.27660.84260.48861.55761.68459.18358.87458.44657.01256.50256.541

-6.981-7.476-8.446-7.750-8.220-8.757-8.233-7.579-8.965-8.901-8.283-10.427-10.897-11.126-10.642-12.588-13.050-11.825-13.314-12.728-14.654-15.436-16.811-15.566-14.900-16.456-16.367-14.924-14.096-14.604-15.503-16.929-14.888-15.411-13.683-13.053-12.806-11.780-11.758-12.245-11.068-13.145-12.938-13.566-12.662

-3.749-5.110-5.451-6.088-5.234-4.272-6.467-7.673-6.760-8.271-8.926-6.337-5.963-6.319-6.320-6.186-6.073-5.792-7.354-8.290-7.263-8.239-7.647-9.580-9.861-10.440-11.846-12.276-11.527-13.517-14.620-14.423-15.999-17.040-15.943-14.762-17.076-16.757-15.228-17.658-17.541-18.351-18.505-19.812-21.043

85.3987.6087.4688.6489.1189.3790.5590.5091.8591.3490.8193.4093.5194.8095.2495.6695.5395.4096.2796.6596.6997.6498.1897.8398.1698.2398.3498.4197.9998.6698.8398.6198.9798.8499.0699.0799.1598.9899.0398.8998.6998.5298.2999.27102.26

RRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRR

NCCOCONCCCCCONCCCCCONCCCONCCONCCCONCCCCCONCCC

CDOE1OE2CONCACBOGCONCACBCONCACBCG1CG2CONCACBOG1CG2CONCACBCGCDOE1OE2CONCACBCGCD1CD2

GLU RGLU RGLU RGLU RGLU RSER RSER RSER RSER RSER RSER RALA RALA RALA RALA RALA RVAL RVAL RVAL RVAL RVAL RVAL RVAL RTHR RTHR RTHR RTHR RTHR RTHR RTHR RGLU RGLU RGLU RGLU RGLU RGLU RGLU RGLU RGLU RLEU RLEU RLEU RLEU RLEU RLEU R

126126126126126127127127127127127128128128128128129129129129129129129130130130130130130130131131131131131131131131131132132132132132132

55.85254.62856.54056.27256.65955.18754.40155.38956.51453.51852.41054.07253.28054.23352.29152.59351.04350.00148.67248.93748.00150.29351.18149.54349.72050.48749.69751.79148.38847.34648.45347.28046.75447.78647.17746.18747.70746.19245.05246.60145.66746.44445.69544.55746.600

-11.335-11.301-10.316-13.649-13.635-14.322-15.089-15.802-14.940-14.151-14.462-12.966-11.874-10.749-11.385-11.270-11.174-10.665-10.733-11.160-9.372-9.209-8.563-8.723-7.344-7.341-7.975-8.120-6.605-7.176-5.287-4.438-4.623-4.215-4.323-5.025-3.706-4.785-5.087-4.772-5.109-5.852-5.895-6.918-6.269

-20.795-20.704-20.869-17.392-16.227-17.835-16.897-15.987-15.779-16.082-15.681-15.792-15.294-14.877-16.357-17.547-15.890-16.765-16.005-14.558-16.008-17.159-16.623-18.164-18.604-19.933-20.935-19.765-18.755-19.059-18.472-18.639-20.063-21.115-22.494-22.643-23.417-17.621-17.952-16.340-15.275-14.186-12.852-12.857-11.679

105.09106.59105.9897.1697.8895.4093.8293.9694.3792.5592.4991.2289.8390.2789.0089.7187.7786.3286.3586.6087.1884.9284.4883.7883.0683.4285.5684.0482.5881.6782.2781.6684.1687.9389.7991.9790.8479.2578.9476.5974.3272.5672.2270.1670.71

RRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRR

COOCONCCOCONCCCONCCCCCONCCOCCONCCCCOOCONCCCCC

CONCACBCGCDOE1NE2CONCACOCBSGNCACBCG2CG1CD1CONCACBCGCD2CE2CE3CD1NE1CZ2CZ3CH2CONCACBCGCD2ND1

LEU RLEU RGLN RGLN RGLN RGLN RGLN RGLN RGLN RGLN RGLN RCYS RCYS RCYS RCYS RCYS RCYS RILE RILE RILE RILE RILE RILE RILE RILE RTRP RTRP RTRP RTRP RTRP RTRP RTRP RTRP RTRP RTRP RTRP RTRP RTRP RTRP RHIS RHIS RHIS RHIS RHIS RHIS R

132132133133133133133133133133133134134134134134134135135135135135135135135136136136136136136136136136136136136136136137137137137137137

45.01445.55543.82943.09242.96742.87343.18142.31644.49941.70241.08741.23239.92038.96039.35140.10141.16037.67036.65135.92434.51336.68436.04435.65235.21435.32534.42634.89034.30934.36233.69834.88433.61333.22933.57934.76334.10132.97232.56632.17230.80030.30330.87530.19132.201

-3.859-3.191-3.521-2.388-1.312-1.889-0.798-0.179-0.562-2.801-3.744-2.078-2.382-1.204-0.096-2.704-4.144-1.507-0.466-0.5540.0510.2350.094-0.668-1.7730.4390.3251.3060.9491.7491.0243.007-0.236-0.2601.5693.5522.8300.6141.751-0.466-0.300-1.640-1.874-2.030-2.030

-14.684-13.812-15.225-14.678-15.759-17.172-18.172-18.770-18.329-14.184-14.665-13.152-12.597-12.765-13.109-11.113-10.850-12.551-12.585-13.929-13.804-15.002-16.383-11.443-11.154-10.754-9.612-8.532-7.214-6.011-4.991-5.728-6.877-5.572-3.722-4.462-3.454-10.000-10.199-10.142-10.621-11.161-12.533-13.744-12.764

73.8973.4074.0073.5876.1279.1081.2582.2381.6671.5272.0468.8566.7564.3163.7868.3870.3461.8558.3657.9454.7457.5058.9657.9558.2556.2456.6155.5053.5454.0254.0755.3554.3954.8654.2955.5754.5756.9058.0556.9156.0355.2354.7155.2255.84

RRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRR

CONCCCCONCONCCOCSNCCCCCCONCCCCCCCNCCCCONCCCCN

CE1NE2CONCACBCGOD1ND2CONCACBCGCD1CD2CONCACBOGCONCACBCGCD1CE1CD2CE2CZOHCONCACBCGSDCEC

HIS RHIS RHIS RHIS RASN RASN RASN RASN RASN RASN RASN RASN RLEU RLEU RLEU RLEU RLEU RLEU RLEU RLEU RSER RSER RSER RSER RSER RSER RTYR RTYR RTYR RTYR RTYR RTYR RTYR RTYR RTYR RTYR RTYR RTYR RMET RMET RMET RMET RMET RMET RMET R

137137137137138138138138138138138138139139139139139139139139140140140140140140141141141141141141141141141141141141142142142142142142142

32.31231.12629.84029.58629.33028.22726.99925.74924.82925.72928.55927.68929.88130.37429.86230.33429.99831.84129.93929.73929.77529.16127.85726.75230.04830.17330.56131.50430.76430.27031.01430.47028.98428.44829.18728.68632.56232.36333.72934.86636.08737.37838.40837.16735.114

-2.281-2.2870.183-0.4871.4151.9221.0501.8051.2723.0951.9521.9761.9311.9193.1634.5055.6734.5820.6510.662-0.460-1.676-1.904-1.372-2.920-3.762-3.062-4.140-5.360-5.103-5.507-5.399-4.600-4.488-4.867-4.663-3.673-2.768-4.322-3.989-3.829-3.604-2.330-1.030-5.094

-14.080-14.693-9.529-8.535-9.739-8.924-9.197-8.827-8.212-9.205-7.426-6.563-7.145-5.763-5.020-5.599-4.669-5.839-5.005-3.799-5.765-5.226-6.005-5.276-5.404-4.521-6.650-6.975-7.555-8.947-10.064-11.345-9.136-10.409-11.512-12.784-7.969-8.768-7.860-8.702-7.792-8.578-7.838-7.767-9.727

55.0356.0056.4958.1856.2157.4458.2360.1361.3059.1258.3357.0959.7760.8759.7059.7557.9658.4562.4963.4063.8165.2065.9068.3665.2266.7164.7564.4265.0466.1166.9567.6167.1268.3969.0670.6364.1062.4463.9965.4867.2170.8177.7273.3666.17

RRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRR

CNCONCCCONCONCCCCCCONCCOCONCCCCCCCCOCONCCCSCC

ONCACBCGCDCENZCONCACOCBSGNCACBOGCONCACBCGCD2CE2CE3CD1NE1CZ2CZ3CH2CONCACBCGCD1CD2CON

MET RLYS RLYS RLYS RLYS RLYS RLYS RLYS RLYS RLYS RCYS RCYS RCYS RCYS RCYS RCYS RSER RSER RSER RSER RSER RSER RTRP RTRP RTRP RTRP RTRP RTRP RTRP RTRP RTRP RTRP RTRP RTRP RTRP RTRP RLEU RLEU RLEU RLEU RLEU RLEU RLEU RLEU RPRO R

142143143143143143143143143143144144144144144144145145145145145145146146146146146146146146146146146146146146147147147147147147147147148

35.14835.22835.48334.40134.35234.20233.22431.85436.88537.24137.71739.09039.33438.75440.02239.86940.18940.55540.24338.84942.05542.76942.52643.95944.62444.41843.48143.65842.53245.12044.71842.90741.77741.96744.36443.59645.62846.09546.53645.33645.71744.63047.21747.90247.344

-6.274-4.675-5.639-5.434-6.571-6.060-6.905-6.602-5.425-4.354-6.477-6.377-7.295-8.366-6.762-5.642-6.811-7.578-6.718-6.438-7.818-7.484-8.426-8.386-8.758-10.196-10.743-12.150-10.170-11.294-12.484-12.940-10.959-12.353-9.384-10.217-9.261-10.155-9.336-8.822-7.748-9.929-11.057-10.801-12.163

-9.414-10.996-12.054-13.123-14.136-15.569-16.390-15.994-12.641-13.113-12.519-12.994-14.192-14.315-11.845-10.436-15.106-16.284-17.511-17.578-16.286-15.352-17.386-17.558-16.236-15.951-14.999-14.994-14.162-16.505-15.980-14.138-13.310-13.296-18.607-19.071-19.008-20.040-21.253-22.059-23.080-22.834-19.564-18.580-20.303

66.9166.3667.0567.9269.1971.2771.1671.4366.6665.9767.0768.2868.2468.1668.9871.3069.4371.0670.6270.8073.0474.3674.6176.4674.0172.3470.7669.2669.7871.2469.8969.5470.5270.2278.9078.8081.8384.1584.2284.9784.5384.2785.7485.9887.39

RRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRR

ONCCCCCNCONCCOCSNCCOCONCCCCCCCNCCCCONCCCCCCON

CDCACBCGCONCACONCACBCONCACBCONCACBCONCACBCGCD1CE1CD2CE2CZOHCONCACBOG1CG2CON

PRO RPRO RPRO RPRO RPRO RPRO RGLY RGLY RGLY RGLY RARG RARG RARG RARG RARG RTHR RTHR RTHR RTHR RTHR RASN RASN RASN RASN RASN RTYR RTYR RTYR RTYR RTYR RTYR RTYR RTYR RTYR RTYR RTYR RTYR RTHR RTHR RTHR RTHR RTHR RTHR RTHR RLEU R

148148148148148148149149149149150150150150150151151151151151157157157157157158158158158158158158158158158158158159159159159159159159160

46.55848.40347.96546.69149.75649.80650.87452.14553.24254.23453.06254.18154.95554.12253.43154.91654.47555.38453.03052.70346.43245.11244.31445.24546.05144.43344.67644.57945.40244.76445.49246.78347.51246.86947.58443.74242.57744.40643.62843.87243.45343.03543.97845.13742.912

-12.564-13.171-14.454-14.155-12.659-11.662-13.358-12.622-12.878-12.169-13.955-14.608-13.873-16.106-16.717-16.690-17.936-18.215-17.751-17.915-21.051-20.618-21.852-19.634-19.808-18.554-17.413-16.126-16.255-16.400-16.312-16.050-15.976-16.109-16.043-17.356-17.732-16.859-16.313-17.106-18.448-16.509-14.858-14.475-14.036

-21.455-20.129-20.828-21.610-20.686-21.387-20.341-20.211-21.246-21.354-22.026-22.661-23.754-22.658-23.454-21.738-21.146-19.955-20.676-19.507-14.609-14.145-13.723-12.976-12.081-13.024-12.133-12.968-14.214-15.442-16.622-14.174-15.356-16.571-17.752-10.910-10.921-9.850-8.746-7.471-7.690-6.329-8.503-8.413-8.456

87.8688.1988.4088.4289.6289.7791.1892.5193.6294.7493.0192.2691.4191.8492.3690.4589.1988.8087.9488.0585.8884.2084.0082.5082.3279.5377.4376.4475.2074.3874.6775.4175.5275.1476.4375.9775.9674.6473.1873.2573.0372.7271.4871.0769.18

RRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRR

CCCCCONCCONCCCONCCCONCCCONCCCCCCCCOCONCCOCCON

CACBCGCD1CD2CONCACBCGCD1CE1CD2CE2CZOHCONCACBCGCD1CE1CD2CE2CZOHCONCACBCGCD2CE2CE3CD1NE1CZ2CZ3CH2CO

LEU RLEU RLEU RLEU RLEU RLEU RLEU RTYR RTYR RTYR RTYR RTYR RTYR RTYR RTYR RTYR RTYR RTYR RTYR RTYR RTYR RTYR RTYR RTYR RTYR RTYR RTYR RTYR RTYR RTYR RTYR RTRP RTRP RTRP RTRP RTRP RTRP RTRP RTRP RTRP RTRP RTRP RTRP RTRP RTRP R

160160160160160160160161161161161161161161161161161161161162162162162162162162162162162162162163163163163163163163163163163163163163163

43.08142.09342.18141.75841.32842.82341.82343.82743.67844.90545.18146.04946.37944.67945.00045.82946.08343.61744.10442.95442.86541.65940.39039.79538.58739.76638.56437.97936.79442.72942.15543.33743.26044.63644.60145.07744.87345.62444.14544.28145.23245.98245.77842.82043.177

-12.640-11.786-10.300-9.348-9.945-12.446-12.896-11.837-11.470-11.973-13.444-13.864-15.212-14.394-15.739-16.155-17.501-9.948-9.205-9.480-8.045-7.510-8.009-7.315-7.747-9.144-9.584-8.896-9.345-7.701-8.431-6.564-6.139-6.324-5.849-4.565-4.558-3.452-6.563-5.856-3.438-2.334-2.329-4.677-3.825

-8.082-8.887-8.500-9.625-7.286-6.590-6.047-5.927-4.522-3.713-3.882-4.886-5.022-2.979-3.120-4.154-4.369-4.413-5.258-3.355-3.159-3.938-3.338-2.288-1.761-3.854-3.321-2.274-1.719-1.680-0.884-1.3110.0610.7122.1222.6034.0111.9853.2474.4014.7482.7234.1150.156-0.642

67.2666.0163.7761.5561.9166.3465.0166.5766.2866.7668.3868.3569.7469.1769.1869.8970.2965.4564.1664.7266.4865.2763.1161.9461.7462.3460.2360.1058.6568.0367.3469.6371.1971.7771.5571.7671.7372.1571.6572.2172.7272.4172.8972.3172.04

RRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRR

CCCCCCONCCCCCCCCOCONCCCCCCCCOCONCCCCCCCNCCCCO

NCACBCGCD2ND1CE1NE2CONCACBCONCACBOGCONCACBCGCD1CD2CONCACBCONCACBCONCACBCG2CG1CD1

HIS RHIS RHIS RHIS RHIS RHIS RHIS RHIS RHIS RHIS RARG RARG RARG RARG RARG RSER RSER RSER RSER RSER RSER RLEU RLEU RLEU RLEU RLEU RLEU RLEU RLEU RGLU RGLU RGLU RGLU RGLU RLYS RLYS RLYS RLYS RLYS RILE RILE RILE RILE RILE RILE R

164164164164164164164164164164165165165165165166166166166166166167167167167167167167167168168168168168169169169169169170170170170170170

41.96141.63740.20239.84140.54338.68538.69139.79241.74841.50342.17942.37642.92541.07341.03839.95638.68537.53236.55438.56737.60739.58039.57039.57138.69439.28337.28840.77041.70440.69941.78041.16742.80544.00142.27243.13442.89842.83041.74043.88143.70144.98244.81246.13547.446

-4.446-3.058-2.794-1.359-0.215-0.9780.3690.853-2.882-3.805-1.699-1.632-0.263-1.920-2.137-1.909-2.195-1.790-1.082-3.676-4.135-4.444-5.871-6.633-5.962-6.081-6.558-6.292-5.535-7.540-8.060-9.007-8.814-8.559-9.807-10.648-12.101-10.475-10.102-10.711-10.725-11.284-11.438-10.307-11.014

1.1461.5061.0571.3200.9411.9211.8871.3053.0183.7733.4834.9285.3175.6806.8774.9295.5894.6655.4255.9466.5545.5175.8044.4803.4222.0153.3536.6506.8857.1467.9709.0007.1247.1716.4005.5946.0084.1083.6913.3151.8821.273-0.2521.5151.859

73.9976.0977.4178.4578.6678.8477.9878.6876.7777.2977.8079.1277.2280.0980.1681.2182.0982.1183.1783.2783.8583.5183.7184.2384.4784.8085.4484.0884.1284.4484.3683.8984.5284.9684.0983.4583.3482.7183.0681.3180.4679.7479.2979.8178.12

RRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRR

NCCCCNCNCONCCCONCCOCONCCCCCCONCCCONCCCONCCCCC

CONCACBCGCD2ND1CE1NE2CONCACBCGCDOE1NE2CONCACOCBSGNCACBCONCACBCGOD1ND2CONCACBCG2CG1

ILE RILE RHIS RHIS RHIS RHIS RHIS RHIS RHIS RHIS RHIS RHIS RGLN RGLN RGLN RGLN RGLN RGLN RGLN RGLN RGLN RCYS RCYS RCYS RCYS RCYS RCYS RGLU RGLU RGLU RGLU RGLU RASN RASN RASN RASN RASN RASN RASN RASN RILE RILE RILE RILE RILE R

170170171171171171171171171171171171172172172172172172172172172173173173173173173174174174174174175175175175175175175175176176176176176

42.50442.23141.73640.56139.37338.68437.44739.17538.26037.21540.79341.75239.89139.95939.79941.09540.75839.85141.51238.77037.61339.04537.94737.52138.33138.41337.18636.18335.64935.51534.29433.31534.12234.64934.10232.61931.94132.12334.79433.90335.93536.24136.44237.88836.217

-11.587-12.629-11.076-11.808-10.829-10.796-11.354-10.114-10.249-10.986-12.475-12.194-13.443-14.228-15.694-16.484-17.862-18.545-18.244-13.889-14.003-13.461-13.228-14.514-15.375-12.180-11.883-14.625-15.956-16.476-16.121-16.337-15.983-15.056-13.645-13.789-14.534-13.187-15.623-16.274-15.304-16.076-17.553-17.994-17.776

1.5062.0890.5290.038-0.0141.3321.7022.3953.3762.991-1.345-2.063-1.669-2.915-2.481-2.365-1.831-2.282-0.781-3.826-3.434-5.085-6.011-6.734-7.055-7.026-8.320-6.935-7.092-5.655-7.778-7.070-9.167-10.196-10.052-9.833-10.541-8.731-11.650-12.194-12.313-13.533-13.218-13.527-11.719

80.5080.8580.2980.3280.1080.1880.2981.1080.5880.4481.2580.7382.6984.3585.6686.7987.2686.5986.8485.7586.5787.0688.5889.4589.2088.1288.2991.0993.0692.7894.8695.2196.5198.1097.6998.1198.8597.6198.9199.6099.69100.40101.08101.79100.88

RRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRR

CONCCCCNCNCONCCCCONCONCCOCSNCCCONCCCONCONCCCC

CD1CONCACBCGCD1CD2CE1CE2CZCONCACBCGCDNECZNH1NH2CONCACBCGCDOE1OE2CONCACONCACBCGCDOE1NE2

ILE RILE RILE RPHE RPHE RPHE RPHE RPHE RPHE RPHE RPHE RPHE RPHE RPHE RARG RARG RARG RARG RARG RARG RARG RARG RARG RARG RARG RGLU RGLU RGLU RGLU RGLU RGLU RGLU RGLU RGLU RGLY RGLY RGLY RGLY RGLN RGLN RGLN RGLN RGLN RGLN RGLN R

176176176177177177177177177177177177177177178178178178178178178178178178178179179179179179179179179179180180180180181181181181181181181

35.83537.28238.47136.85135.53334.52634.89634.85235.12035.01235.27535.21735.63634.67036.85737.18537.43638.35139.34538.68338.99140.22137.99936.15134.97036.63835.77335.40533.99933.67834.58332.51236.45536.83336.59237.42138.81238.98739.81841.19042.13543.45344.43545.60043.907

-19.220-15.435-15.481-14.872-15.078-14.079-12.665-12.249-11.739-10.906-10.393-9.969-14.881-14.993-14.522-14.362-15.735-15.629-16.797-17.951-18.243-18.048-18.428-13.580-13.903-12.501-11.734-10.413-10.453-9.128-8.325-8.909-11.453-10.331-12.538-12.461-13.017-14.171-12.151-12.569-11.897-12.656-11.767-12.075-10.593

-11.403-14.470-14.194-15.645-16.267-15.684-16.040-17.367-15.031-17.678-15.350-16.673-17.792-18.554-18.227-19.648-20.265-21.483-21.562-22.159-23.433-23.871-24.310-20.471-20.532-21.117-22.012-21.330-20.727-20.073-19.891-19.746-23.353-23.662-24.139-25.343-25.044-24.678-25.221-24.929-25.932-26.116-26.849-27.043-27.251

101.03100.57100.09100.98101.31101.94103.06103.48103.36102.99103.34103.07101.05100.84101.03101.14101.04101.47102.67104.10104.33104.55104.03101.18101.57100.71100.14100.45100.59100.07100.0999.8499.7299.7498.9297.3396.4496.8195.6494.6093.4891.7991.0590.4791.76

RRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRR

CCONCCCCCCCCCONCCCCNCNNCONCCCCOOCONCCONCCCCON

CONCACBCGCD1CE1CD2CE2CZOHCONCACBCGCD1CD2CE1CE2CZCONCACONCACOCBSGNCACBOGCONCACBCG

GLN RGLN RTYR RTYR RTYR RTYR RTYR RTYR RTYR RTYR RTYR RTYR RTYR RTYR RPHE RPHE RPHE RPHE RPHE RPHE RPHE RPHE RPHE RPHE RPHE RGLY RGLY RGLY RGLY RCYS RCYS RCYS RCYS RCYS RCYS RSER RSER RSER RSER RSER RSER RPHE RPHE RPHE RPHE R

181181182182182182182182182182182182182182183183183183183183183183183183183184184184184185185185185185185186186186186186186187187187187

41.59442.56440.83541.11440.41440.89239.96040.30942.19942.55341.61341.93540.58639.68341.21740.64941.70041.81742.56141.31342.81241.57042.32140.28240.91839.19938.72138.09738.00337.69037.16936.51337.07238.35137.84235.26734.55333.16233.28834.41434.22034.55834.27735.59636.588

-12.197-12.693-11.252-10.850-9.515-8.460-7.756-6.563-7.976-6.787-6.079-4.857-11.879-12.660-11.890-12.619-13.609-14.796-14.689-16.027-15.822-17.158-17.061-11.627-10.596-11.934-10.948-11.592-12.806-10.718-11.211-10.091-9.024-11.784-12.999-10.349-9.318-9.134-8.740-9.655-10.797-8.610-8.787-9.010-7.932

-23.501-22.947-22.922-21.550-21.292-22.224-22.982-23.595-22.127-22.749-23.476-24.029-20.547-20.826-19.356-18.222-17.704-18.620-19.789-18.226-20.556-18.999-20.164-17.109-16.931-16.373-15.388-14.131-14.001-13.175-11.888-11.058-10.855-11.104-9.871-10.589-9.830-10.442-11.808-8.338-7.939-7.499-6.077-5.328-5.661

94.4794.0493.9192.8193.0292.8292.4892.4493.1392.7192.0191.1592.2692.3691.3790.2590.9191.4191.7891.1291.3691.1391.2689.1488.9887.7286.3485.8686.3485.1483.6181.5681.3085.1489.0078.9076.8775.9375.3976.0177.1674.9274.7973.2572.03

RRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRR

CONCCCCCCCCOCONCCCCCCCCCONCCONCCOCSNCCOCONCCC

CD1CD2CE1CE2CZCONCACBCGOD1OD2CONCACBCGCD1CD2CONCACBOG1CG2CONCACBCGCDCENZCONCACBCG1CG2C

PHE RPHE RPHE RPHE RPHE RPHE RPHE RASP RASP RASP RASP RASP RASP RASP RASP RLEU RLEU RLEU RLEU RLEU RLEU RLEU RLEU RTHR RTHR RTHR RTHR RTHR RTHR RTHR RLYS RLYS RLYS RLYS RLYS RLYS RLYS RLYS RLYS RVAL RVAL RVAL RVAL RVAL RVAL R

187187187187187187187188188188188188188188188189189189189189189189189190190190190190190190191191191191191191191191191192192192192192192

37.50336.72038.56237.78538.70933.53333.63232.73231.94330.99229.93329.26529.79232.81233.70732.53133.32134.35635.76136.64835.74232.39132.42231.45330.48929.05628.69428.16430.84331.43730.40730.89432.42633.38834.85534.96836.36430.46230.06230.29731.28031.43530.32232.73130.689

-8.143-6.833-7.262-5.952-6.164-7.590-6.461-7.881-6.820-7.454-8.252-9.057-8.069-5.775-6.088-4.502-3.580-2.914-2.840-1.751-2.541-2.574-1.413-3.061-2.291-2.733-3.084-1.538-1.908-2.489-0.7820.095-0.031-0.275-0.386-0.0690.0351.3591.6041.9912.9423.5714.5344.2463.764

-6.686-4.825-6.861-5.009-6.023-5.486-5.948-4.446-3.832-2.819-3.559-2.910-4.765-3.137-2.352-3.479-2.691-3.632-3.015-3.654-1.516-2.088-2.462-1.220-0.756-0.767-2.088-0.3430.5791.4680.5351.3141.6650.5161.0112.5042.9090.829-0.3221.8732.0870.7130.2860.8333.176

70.7771.7670.3170.7970.2575.4775.7576.3877.2977.9779.7179.8380.4078.2577.9879.8181.2879.9578.5677.8678.0183.8985.1485.9989.3290.5492.8590.9890.5289.9391.7992.7192.7593.3994.0094.6595.2493.0694.3893.4493.5393.7292.9893.2893.63

RRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRR

CCCCCCONCCCOOCONCCCCCCONCCOCCONCCCCCNCONCCCCC

ONCACBCONCACBCONCACBCONCACBCGCD1CD2CE1CE2CZCONCACBCGCDOE1OE2CONCACBCONCACBCG

VAL RSER RSER RSER RSER RSER RSER RSER RSER RSER RSER RPHE RPHE RPHE RPHE RPHE RPHE RPHE RPHE RPHE RPHE RPHE RPHE RPHE RPHE RPHE RPHE RGLU RGLU RGLU RGLU RGLU RGLU RGLU RGLU RGLU RGLN RGLN RGLN RGLN RGLN RHIS RHIS RHIS RHIS R

192195195195195195196196196196196197197197197197198198198198198198198198198198198199199199199199199199199199200200200200200201201201201

29.65134.83035.90035.43037.17137.81837.58238.28239.56338.60338.83238.65339.37938.67340.85541.50741.36842.55342.84442.93842.00444.03042.16244.18543.26042.23141.27043.09342.68343.57543.82945.31946.02845.76242.77343.54941.88542.20441.17443.61243.96744.28545.39146.85147.274

3.3005.0675.6196.3676.1157.0545.3495.9026.6814.7043.6084.8656.0286.7515.7096.1634.9194.0823.4154.4184.4075.2605.2656.1116.1202.9092.1562.7261.8862.2343.7323.9573.1434.9430.369-0.104-0.402-1.807-2.437-1.900-1.288-2.810-3.514-3.159-3.528

3.7005.0445.8907.1415.1855.5904.1603.0063.4492.1052.5970.7870.271-0.8640.058-0.8681.0390.8512.1963.2734.3003.3245.3814.4055.439-0.0850.109-1.119-2.249-3.415-3.497-3.496-2.922-4.082-1.990-1.171-2.688-2.879-3.820-3.458-4.445-2.734-3.381-3.012-1.597

93.6393.3293.7392.6292.8992.9892.6192.2192.1892.0591.9191.6989.9489.2889.6289.8688.1587.6888.9990.0690.8090.3991.2690.9591.4986.5786.6784.7382.6183.3585.7888.8891.3988.2779.6680.1077.5675.2274.1773.8973.9972.0169.7072.0774.38

RRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRR

ONCCCONCCCONCCCONCCCCCCCCCONCCCCOOCONCCCONCCC

CD2ND1CE1NE2CONCACBOGCONCACBCONCACBCONCACBCGSDCECONCACBCG1CG2CONCACBCGCDCENZC

HIS RHIS RHIS RHIS RHIS RHIS RSER RSER RSER RSER RSER RSER RGLN RGLN RGLN RGLN RGLN RILE RILE RILE RILE RILE RMET RMET RMET RMET RMET RMET RMET RMET RVAL RVAL RVAL RVAL RVAL RVAL RVAL RLYS RLYS RLYS RLYS RLYS RLYS RLYS RLYS R

201201201201201201202202202202202202203203203203203204204204204204205205205205205205205205206206206206206206206207207207207207207207207

46.77448.59248.90747.84845.00344.00245.75145.32744.49543.09846.53547.59946.32747.39948.20446.85545.85447.50947.01746.51048.13049.09547.99948.96749.96549.40250.70349.67448.31947.11149.20848.79949.72149.50851.15748.96749.96747.90848.23746.92845.91644.80643.62642.37048.838

-2.989-3.870-3.380-2.827-4.779-5.417-5.050-6.188-5.649-5.779-6.973-6.431-8.302-9.168-9.679-10.371-10.977-10.732-11.891-11.420-12.914-12.693-14.052-15.105-15.225-15.843-16.108-16.308-16.438-16.605-17.383-18.755-19.384-18.739-19.192-19.544-19.462-20.307-21.691-22.445-21.599-21.024-21.989-21.243-22.108

-0.388-1.379-0.1740.437-4.170-3.872-5.270-6.091-7.263-6.969-6.619-6.871-6.744-7.251-6.053-8.053-7.702-9.173-9.892-11.254-10.099-10.811-9.402-9.673-8.509-7.222-6.007-4.546-10.013-10.058-10.328-10.495-11.537-12.903-11.105-9.205-8.501-8.873-8.645-8.381-7.591-8.473-8.659-8.795-9.996

75.5875.6875.8976.6567.1265.8765.7665.4965.5966.0765.8964.1566.7567.3866.6968.3666.9170.1172.8571.7674.0573.6975.9678.6279.4481.8182.9282.5879.8379.0681.9284.1884.1184.5384.6385.8185.7187.7289.8288.8387.1884.3283.2181.5491.87

RRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRR

CNCNCONCCOCONCCCONCCCONCCCSCCONCCCCCONCCCCCNC

ONCACBCGOD1OD2CONCACBCONCACBCONCACONCACBCONCACBCONCACBCONCDCACBCGCO

LYS RASP RASP RASP RASP RASP RASP RASP RASP RASN RASN RASN RASN RASN RALA RALA RALA RALA RALA RGLY RGLY RGLY RGLY RLYS RLYS RLYS RLYS RLYS RILE RILE RILE RILE RILE RLYS RLYS RLYS RLYS RLYS RPRO RPRO RPRO RPRO RPRO RPRO RPRO R

207208208208208208208208208209209209209209210210210210210211211211211212212212212212213213213213213214214214214214215215215215215215215

48.71349.54049.96649.74350.31450.55150.42551.43952.31351.68853.07453.64753.91455.11453.27253.98455.32454.17354.01954.35055.68755.97957.14754.94653.50952.63753.08352.08253.89454.08854.45455.21655.93155.44955.51756.28854.16353.26953.98854.69852.98053.30254.36053.02654.099

-21.364-23.245-24.006-25.487-26.476-26.079-27.653-23.684-24.168-22.736-22.593-23.981-21.882-21.672-21.535-20.679-20.490-21.188-22.340-20.070-19.730-18.821-18.479-18.419-18.475-18.475-17.372-16.687-17.246-15.920-16.057-15.382-16.146-14.078-13.243-12.003-12.841-12.542-12.879-13.643-12.057-11.929-12.976-10.687-10.107

-10.971-10.062-8.913-9.287-8.267-7.124-8.606-8.693-9.392-7.775-7.285-6.970-8.310-8.150-9.471-10.372-9.802-11.727-12.136-12.407-12.616-13.853-14.185-14.628-14.380-15.650-13.420-13.538-12.371-11.881-10.403-12.781-13.391-12.885-11.735-12.189-11.268-12.049-9.968-8.962-9.392-7.903-7.554-10.110-10.259

92.7593.3694.5295.1494.5295.0894.4695.3095.2595.4695.8095.9195.8096.4594.7294.1693.3494.1894.2094.3894.6395.2196.2794.9794.2594.9293.5993.8392.4291.1691.3690.2791.1988.6186.2986.2284.2684.2881.5980.1979.5480.0980.4377.5077.69

RRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRR

ONCCCOOCONCCCONCCCONCCONCCCONCCCONCCCONCCCCCO

NCACBOGCONCACBCGCD1CD2CE1CE2CZCONCACBCGOD1ND2CONCACBCG2CG1CD1CONCACBCG1CG2CONCDCACBCG

SER RSER RSER RSER RSER RSER RPHE RPHE RPHE RPHE RPHE RPHE RPHE RPHE RPHE RPHE RPHE RASN RASN RASN RASN RASN RASN RASN RASN RILE RILE RILE RILE RILE RILE RILE RILE RVAL RVAL RVAL RVAL RVAL RVAL RVAL RPRO RPRO RPRO RPRO RPRO R

216216216216216216217217217217217217217217217217217218218218218218218218218219219219219219219219219220220220220220220220221221221221221

51.82851.66051.05451.36150.71249.59451.25350.46351.35152.00553.24751.37953.87252.02453.28449.87650.43448.70948.37847.49947.41146.28248.55047.68546.88247.88247.07247.88947.08949.24549.14245.91246.06344.72543.61542.59541.26442.87943.04642.64043.01943.75642.37743.03543.602

-10.243-8.826-8.795-7.546-8.058-8.459-6.957-6.155-5.718-6.881-7.331-7.498-8.369-8.545-8.979-4.897-4.318-4.460-3.039-3.078-1.735-1.290-1.234-2.335-2.948-1.008-0.2570.7181.4230.171-0.7500.4531.3180.2740.807-0.2220.389-1.1761.8231.4463.0983.6824.0805.4315.276

-10.616-11.042-12.451-13.070-10.081-9.784-9.506-8.580-7.410-6.740-7.192-5.662-6.543-5.008-5.431-9.226-10.167-8.796-9.002-10.262-11.083-11.316-11.638-7.829-7.054-7.739-6.782-6.154-5.015-5.849-4.532-7.427-8.100-6.972-7.625-7.732-7.943-8.784-6.630-5.576-6.931-8.065-6.016-6.332-7.714

75.9974.4074.5275.5873.2072.1272.0071.1671.0571.6472.4371.9671.9272.6572.4569.7169.8169.2267.8268.5669.1468.2469.1167.0467.2765.2862.2261.2660.0060.7461.5960.8060.8559.0558.4958.2457.0358.4559.1858.0159.2259.5159.0959.1760.65

RRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRR

NCCOCONCCCCCCCCCONCCCONCONCCCCCCONCCCCCONCCCC

CONCACBCGCD1CD2CONCACBOG1CG2CONCACBOGCONCACBCGCDNECZNH1NH2CONCACBCG1CG2CONCACBCG

PRO RPRO RLEU RLEU RLEU RLEU RLEU RLEU RLEU RLEU RTHR RTHR RTHR RTHR RTHR RTHR RTHR RSER RSER RSER RSER RSER RSER RARG RARG RARG RARG RARG RARG RARG RARG RARG RARG RARG RVAL RVAL RVAL RVAL RVAL RVAL RVAL RLYS RLYS RLYS RLYS R

221221222222222222222222222222223223223223223223223224224224224224224225225225225225225225225225225225226226226226226226226227227227227

40.91640.36540.30738.86238.40138.86638.15938.42738.33537.14139.17738.76939.80341.11239.94338.58638.60038.76138.63139.94040.97538.19037.99437.98937.47338.65139.76941.05040.78240.83641.21540.46236.26136.18035.24233.96333.58132.23034.62632.92932.68332.27731.17331.41230.200

4.0533.6424.3244.3963.8802.4002.0931.3125.8266.1946.6288.0178.9558.7018.6028.3529.5857.3277.4317.8447.0946.1575.1956.1984.9904.0044.3813.6772.3592.0042.8540.7994.3703.1875.1984.7575.5535.0985.4004.8995.9773.8033.6772.6252.673

-6.228-7.271-5.110-4.976-3.581-3.381-2.020-4.282-5.198-4.797-5.887-6.126-5.469-6.077-3.942-7.661-7.991-8.481-9.949-10.698-10.323-10.509-9.813-11.805-12.554-12.686-13.915-13.667-14.166-15.433-16.406-15.754-11.811-11.400-11.679-11.138-9.962-9.412-9.019-12.171-12.594-12.432-13.343-14.480-15.576

58.5557.9758.6559.4359.0959.8659.9059.5459.5160.1459.0460.5360.1358.8159.9661.1262.1260.4460.0559.1558.9660.3460.3260.2460.0661.4762.3664.7468.2169.7670.9968.9758.9858.2458.0957.6757.0557.9756.3057.2057.6956.0755.3456.4158.70

RRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRR

CONCCCCCCONCCOCCONCCOCONCCCCNCNNCONCCCCCONCCC

CDCENZCONCDCACBCGCONCACBCGOD1OD2CONCDCACBCGCONCDCACBCGCONCACBCGCD2ND1CE1NE2CON

LYS RLYS RLYS RLYS RLYS RPRO RPRO RPRO RPRO RPRO RPRO RPRO RASP RASP RASP RASP RASP RASP RASP RASP RPRO RPRO RPRO RPRO RPRO RPRO RPRO RPRO RPRO RPRO RPRO RPRO RPRO RPRO RHIS RHIS RHIS RHIS RHIS RHIS RHIS RHIS RHIS RHIS RILE R

227227227227227228228228228228228228229229229229229229229229230230230230230230230231231231231231231231232232232232232232232232232232233

30.32329.31529.78829.72529.39928.95329.26327.71627.25528.40826.78226.94925.77824.57523.61923.77322.85724.74523.87524.15522.90222.65522.14921.61821.43921.03220.58520.64521.20919.55819.82020.36318.22518.10817.18415.89815.32616.04017.22615.50916.39417.42414.98414.78914.490

1.3721.2150.1133.6092.6314.7186.0944.6906.1257.0113.8573.6183.4672.9422.4510.9040.4030.1784.0075.1973.6262.2344.6423.8242.5535.3164.9136.4707.2017.1558.5598.4026.7265.9137.2946.7775.9164.5704.3013.3782.4282.9517.9878.8238.130

-16.396-17.612-18.509-12.754-12.202-12.738-13.221-12.075-12.135-12.531-12.908-14.112-12.223-12.833-11.626-11.364-10.684-11.874-13.620-13.521-14.361-14.865-15.096-16.264-15.823-14.361-13.309-14.824-15.948-14.158-14.487-15.906-14.621-15.535-14.050-14.461-13.298-13.111-12.418-13.508-13.135-12.477-14.716-13.855-15.957

60.4261.7664.3754.1553.7552.9151.9752.4552.9052.6152.9853.1853.4753.8354.5955.8656.0554.8253.7954.1853.3952.4751.1252.0853.3150.1149.0249.4147.6249.2348.5548.8750.3649.5751.6555.0158.7564.2366.0166.2166.3367.2354.8655.1155.90

RRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRR

CCNCONCCCCCONCCCOOCONCCCCCONCCCCCONCCCCNCNCON

CACBCG2CG1CD1CONCACBCGCDCENZCONCACBCGOD1ND2CONCACBCGCD1CD2CONCACBOGCONCACBCGCD1CD2CE1

ILE RILE RILE RILE RILE RILE RILE RLYS RLYS RLYS RLYS RLYS RLYS RLYS RLYS RLYS RASN RASN RASN RASN RASN RASN RASN RASN RLEU RLEU RLEU RLEU RLEU RLEU RLEU RLEU RSER RSER RSER RSER RSER RSER RPHE RPHE RPHE RPHE RPHE RPHE RPHE R

233233233233233233233234234234234234234234234234235235235235235235235235236236236236236236236236237237237237237237238238238238238238238

13.66813.48812.52314.82014.82112.29611.65811.88510.55310.61211.36811.31211.77812.3799.4218.3939.5978.6527.4766.3245.9445.7089.29810.3968.5288.7829.08010.17310.18211.5427.5236.3997.6996.5455.8366.7396.9518.1165.9366.2235.3115.6184.6946.7524.900

9.3099.42510.5929.7689.3529.2078.16810.30610.30811.06710.34811.16810.43011.41010.91410.29212.20012.74613.43813.45012.42414.63513.66914.17313.80614.83014.17313.12612.19613.77715.66615.21016.92217.78418.00618.62019.12519.51019.82021.06621.14220.01818.99320.07218.029

-16.230-17.746-18.052-18.450-19.932-15.516-15.524-14.815-14.137-12.787-11.657-10.373-9.129-8.240-15.004-15.238-15.425-16.405-15.735-16.725-17.277-16.867-17.448-17.321-18.543-19.552-20.879-20.782-21.988-20.782-19.730-19.575-20.088-20.314-18.979-18.060-20.925-20.949-21.477-22.176-23.399-24.344-24.509-25.139-25.485

57.9055.9954.7054.0551.1859.5860.7762.9466.6667.9271.2873.3575.7777.0268.0268.1269.3872.1173.5775.2477.1875.8372.5273.5872.3272.1871.3570.8669.2970.3572.5572.5472.9974.1872.8372.5676.0676.0377.5779.6477.7976.6075.5776.2074.70

RRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRR

CCCCCCONCCCCCNCONCCCONCONCCCCCCONCCOCONCCCCCC

CE2CZCONCACBCGCD2ND1CE1NE2CONCACBCONCACBCGOD1OD2CONCACBCGOD1OD2CONCACBCGCD1CD2CONCA

PHE RPHE RPHE RPHE RHIS RHIS RHIS RHIS RHIS RHIS RHIS RHIS RHIS RHIS RASN RASN RASN RASN RASN RASP RASP RASP RASP RASP RASP RASP RASP RASP RASP RASP RASP RASP RASP RASP RASP RLEU RLEU RLEU RLEU RLEU RLEU RLEU RLEU RTYR RTYR R

238238238238239239239239239239239239239239240240240240240241241241241241241241241242242242242242242242242243243243243243243243243244244

6.9516.0265.9925.0416.9336.7307.5628.0879.3357.3738.1649.3477.1808.3476.2046.5727.7057.0266.4448.0868.4008.6457.3396.2957.3679.53110.2059.58310.70611.39012.18512.36812.60310.2729.12311.27611.00011.45810.78811.61210.57411.74112.96310.92811.479

19.10018.07922.29122.37423.24724.52224.53925.93526.32727.05128.09027.68925.66825.99426.25627.23528.07926.48625.48826.97026.25127.27528.06327.51029.21625.21824.82824.71423.87224.58025.77525.86426.59522.49222.08821.76320.44619.39418.03416.88217.70920.24120.18620.17019.957

-26.117-26.297-21.290-20.523-21.387-20.723-19.451-19.238-18.739-19.528-19.201-18.726-21.621-21.715-22.310-23.314-22.739-24.568-24.980-25.210-26.430-27.532-27.722-27.353-28.150-26.253-27.191-25.000-24.616-23.455-23.943-25.151-23.124-24.112-24.167-23.574-23.006-24.018-23.804-24.382-22.327-21.680-21.631-20.611-19.278

75.8275.6281.7182.5484.0586.7688.5590.5791.4991.7092.5892.4387.5287.4488.2988.2488.2588.0288.5187.1686.3087.9587.6788.1588.1285.0485.1782.5780.0680.4381.4881.9181.6378.4479.4675.6973.5272.8472.0971.2972.1172.8173.0871.2770.19

RRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRR

CCCONCCCCNCNCONCCCONCCCOOCONCCCOOCONCCCCCCONC

CBCGCD1CE1CD2CE2CZOHCONCACBCG1CG2CONCACBCGCDOE1NE2CONCACBCGCD2CE2CE3CD1NE1CZ2CZ3CH2CONCACBCGCD

TYR RTYR RTYR RTYR RTYR RTYR RTYR RTYR RTYR RTYR RVAL RVAL RVAL RVAL RVAL RVAL RVAL RGLN RGLN RGLN RGLN RGLN RGLN RGLN RGLN RGLN RTRP RTRP RTRP RTRP RTRP RTRP RTRP RTRP RTRP RTRP RTRP RTRP RTRP RTRP RGLU RGLU RGLU RGLU RGLU R

244244244244244244244244244244245245245245245245245246246246246246246246246246247247247247247247247247247247247247247247248248248248248

10.47711.14912.30712.89110.59011.17812.32312.89111.69610.78412.97213.23814.34414.62913.90213.57314.27012.99713.11511.73911.83110.6919.69810.87213.55113.06814.53615.09216.10817.39417.79619.14017.14018.52219.59619.78017.78319.10715.73516.01215.92916.48715.53616.04415.069

20.51620.76121.53421.82920.27320.55921.32921.64018.46817.65318.11516.72116.18714.71716.28016.52917.31415.44115.14015.39615.84616.79616.92217.48813.68412.76013.49312.14411.89012.59913.86214.10014.79812.10712.94215.26615.95716.19811.88412.77610.57710.1489.1018.4877.423

-18.267-16.963-16.907-15.679-15.782-14.558-14.503-13.282-18.999-19.015-18.762-18.435-19.341-19.009-20.790-16.954-16.315-16.403-14.975-14.333-12.870-12.544-13.247-11.400-14.765-15.412-13.858-13.688-14.805-14.573-15.156-14.767-15.948-13.876-13.960-15.160-16.349-15.942-12.316-11.535-12.040-10.767-10.183-8.879-8.426

72.0674.3075.3576.0175.1274.7975.9275.9268.9267.4868.1966.9967.1465.5465.1566.2466.4465.5665.4967.5170.0671.1170.5470.8664.6465.5263.7862.3461.1860.7960.0660.1058.8760.7459.4358.4957.7857.9362.2761.1362.9264.6166.8272.4475.78

RRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRR

CCCCCCCOCONCCCCCONCCCCONCONCCCCCCCNCCCCONCCCC

OE1OE2CONCACBCGOD1ND2CONCDCACBCGCONCACBCGCDOE1NE2CONCACBCGOD1ND2CONCACBCGCD1CD2CE1CE2CZ

GLU RGLU RGLU RGLU RASN RASN RASN RASN RASN RASN RASN RASN RPRO RPRO RPRO RPRO RPRO RPRO RPRO RGLN RGLN RGLN RGLN RGLN RGLN RGLN RGLN RGLN RASN RASN RASN RASN RASN RASN RASN RASN RPHE RPHE RPHE RPHE RPHE RPHE RPHE RPHE RPHE R

248248248248249249249249249249249249250250250250250250250251251251251251251251251251252252252252252252252252253253253253253253253253253

14.88114.48317.88118.07918.88220.22821.20721.37521.43721.46920.33119.46921.40922.44421.67422.94623.26021.84022.53321.13521.04520.36719.46718.81017.61419.66922.40622.51123.45424.78025.67825.16025.58024.28125.51326.55225.00325.62425.93326.91126.45228.26927.36029.16428.712

7.2716.7669.5478.57810.1929.63810.66911.80911.62713.0268.3408.0007.5847.8006.3615.7376.4326.6617.5805.8616.1674.9875.4234.2074.1443.2046.5007.3925.7235.8774.7143.3862.3283.4367.1617.5227.8149.0489.0387.9576.6558.2565.6357.2215.920

-7.227-9.286-10.959-11.678-10.330-10.413-9.845-10.817-12.030-10.253-9.611-8.814-9.878-10.874-9.133-9.701-11.023-7.639-7.229-6.818-5.391-4.687-3.526-2.909-2.674-2.634-4.729-3.905-5.102-4.463-4.874-4.394-4.860-3.381-4.868-4.312-5.924-6.322-7.808-8.123-8.263-8.278-8.533-8.566-8.691

76.8277.1763.4062.3063.1663.4161.8461.5861.6161.7063.6663.4863.5763.2764.1163.5963.9565.1564.7366.0366.2869.3374.1975.9576.8976.3663.7863.3361.6660.5259.3959.9158.5757.3960.2659.2359.7759.1856.7655.9255.7855.3955.1856.0556.84

RRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRR

OOCONCCCONCONCCCCCONCCCCONCONCCCONCONCCCCCCCC

CONCACBCG2CG1CD1CONCACBOGCONCACBCGCDNECZNH1NH2CONCACOCBSGNCACBCGCD1CD2CONCACBCG

PHE RPHE RILE RILE RILE RILE RILE RILE RILE RILE RSER RSER RSER RSER RSER RSER RARG RARG RARG RARG RARG RARG RARG RARG RARG RARG RARG RCYS RCYS RCYS RCYS RCYS RCYS RLEU RLEU RLEU RLEU RLEU RLEU RLEU RLEU RPHE RPHE RPHE RPHE R

253253254254254254254254254254255255255255255255256256256256256256256256256256256257257257257257257258258258258258258258258259259259259

24.72323.50925.38424.68425.33526.79125.38926.00124.92625.96923.99623.95622.64422.45825.12225.59925.58326.65326.80827.23627.69427.68626.57725.36026.69327.93828.88527.98329.16629.17830.14529.18629.65028.14327.91826.65526.50425.16027.53527.78327.27528.10127.73928.97129.726

10.18910.08811.30112.48312.92812.41114.44714.97113.48313.48214.30915.08015.83116.74615.99516.07016.75917.64318.70218.15419.17818.48218.20118.53017.61116.92617.56915.63614.84514.29013.65513.67314.13214.51113.91313.15711.93411.34610.90114.98416.07514.60715.31815.74817.012

-6.034-5.964-5.843-5.501-4.205-4.197-4.172-2.876-6.590-7.255-6.862-8.086-8.045-9.147-8.454-9.628-7.484-7.758-6.582-5.258-4.274-2.990-2.279-2.655-1.141-8.025-8.396-7.866-8.206-9.641-10.058-7.249-5.568-10.377-11.614-11.529-10.673-10.859-11.209-12.653-12.364-13.826-15.113-15.963-15.450

59.8961.2260.1559.9562.0363.1862.6462.2459.0759.1658.7458.9458.9462.5158.4258.5157.5055.7557.3958.4258.5860.4160.8859.8160.0353.8452.4452.6852.7251.1450.4754.1960.7448.4047.8246.6247.5748.2545.8647.1246.6345.5545.7046.6649.54

RRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRR

CONCCCCCCONCCOCONCCCCNCNNCONCCOCSNCCCCCCONCCC

CD1CD2CE1CE2CZCONCACBCGCD1CE1CD2CE2CZOHCONCACBCGCDOE1OE2CONCACBCG1CG2CONCACBCGCDOE1OE2CON

PHE RPHE RPHE RPHE RPHE RPHE RPHE RTYR RTYR RTYR RTYR RTYR RTYR RTYR RTYR RTYR RTYR RTYR RTYR RGLU RGLU RGLU RGLU RGLU RGLU RGLU RGLU RGLU RVAL RVAL RVAL RVAL RVAL RVAL RVAL RGLU RGLU RGLU RGLU RGLU RGLU RGLU RGLU RGLU RVAL R

259259259259259259259260260260260260260260260260260260260261261261261261261261261261262262262262262262262263263263263263263263263263264

29.24430.98129.90231.69031.15226.84526.92826.09725.09123.65023.57923.86123.85223.24123.13323.54423.42225.15825.51824.64924.35625.29426.12327.23328.38426.91822.85222.35622.14820.81620.00318.56120.24420.66120.80820.26419.85520.21720.07219.92520.90618.85518.34017.38518.129

17.72517.45718.91618.72219.36614.45013.26215.06314.34714.67514.80615.96716.06613.71813.83114.92514.96714.46315.47713.43913.55512.70313.41712.67613.29311.55113.31112.28014.28814.13915.25815.07515.53614.11215.10512.97112.64711.11910.7499.2238.6288.51312.85212.31213.621

-14.274-16.045-13.682-15.533-14.260-15.962-15.914-16.918-17.606-17.082-15.612-15.000-13.479-14.809-13.473-12.762-11.316-19.098-19.703-19.772-21.222-21.907-22.942-23.736-23.854-24.307-21.527-21.353-22.026-22.348-21.830-22.070-20.345-23.893-24.535-24.382-25.633-25.870-27.461-27.656-28.122-27.239-26.019-25.460-27.087

49.6950.8650.5850.2850.4546.1246.4045.2345.8446.7049.3650.5052.7849.2651.5553.0856.1045.8246.9645.3944.7042.6846.0448.5848.4850.7644.6844.5143.0744.2943.8543.8743.7345.6945.9547.4249.9651.5653.0155.4256.5957.6250.7548.9952.50

RRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRR

CCCCCCONCCCCCCCCOCONCCCCOOCONCCCCCONCCCCGOCON

CACBCG1CG2CONCACBCGOD1ND2CONCACBCGOD1ND2CONCACBOGCONCACBCGCDOE1NE2CONCACBOG1CG2CON

VAL RVAL RVAL RVAL RVAL RVAL RASN RASN RASN RASN RASN RASN RASN RASN RASN RASN RASN RASN RASN RASN RASN RASN RSER RSER RSER RSER RSER RSER RGLN RGLN RGLN RGLN RGLN RGLN RGLN RGLN RGLN RTHR RTHR RTHR RTHR RTHR RTHR RTHR RGLU R

264264264264264264265265265265265265265265266266266266266266266266267267267267267267268268268268268268268268268269269269269269269269270

16.77316.29514.77116.56916.71117.42915.83115.49115.62616.96917.77517.22714.08613.08313.99412.74212.92511.57910.77411.33012.35412.97511.31310.8809.77810.13910.35010.3189.8939.3258.5467.1766.3835.2327.06810.39310.33111.36812.44612.97813.48311.84613.55914.25113.698

13.87815.30915.52115.77113.63614.29212.72912.53311.06410.48911.2189.19013.02312.83113.72214.15415.58916.25515.93817.20413.24813.23412.43111.51110.61810.20412.26911.77313.50714.31215.45915.01316.23516.19117.38014.85214.66415.59116.09117.41517.21918.44615.04914.99514.183

-27.641-27.377-27.633-25.785-29.117-29.756-29.615-31.017-31.500-31.183-30.646-31.394-31.342-30.585-32.460-33.058-33.554-33.675-34.546-32.755-34.221-35.275-33.987-35.034-34.462-33.149-36.255-37.370-35.990-37.060-36.429-35.922-35.535-35.127-35.696-38.017-39.228-37.453-38.304-37.738-36.420-37.673-38.477-39.482-37.451

54.1153.6251.7952.9555.8056.0758.1661.4360.7061.6361.7661.4763.8564.6066.7369.5071.2273.1774.2073.7471.2970.9973.9076.2476.1778.7177.6678.4579.0180.9883.0786.6588.8889.3189.8981.0881.4480.3978.8879.4279.0878.9977.1976.9175.45

RRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRR

CCCCCONCCCONCONCCCONCONCCOCONCCCCONCONCCOCCON

CACBCGCDOE1OE2CONCACBOG1CG2CONCACBCGCD2ND1CE1NE2CONCACBCGOD1ND2CONCACBCG1CG2CONCACBCGCD1

GLU RGLU RGLU RGLU RGLU RGLU RGLU RGLU RTHR RTHR RTHR RTHR RTHR RTHR RTHR RHIS RHIS RHIS RHIS RHIS RHIS RHIS RHIS RHIS RHIS RASN RASN RASN RASN RASN RASN RASN RASN RVAL RVAL RVAL RVAL RVAL RVAL RVAL RPHE RPHE RPHE RPHE RPHE R

270270270270270270270270271271271271271271271272272272272272272272272272272273273273273273273273273274274274274274274274275275275275275

14.70614.89515.16014.61115.30813.48616.03117.05315.99017.18916.96617.01618.05917.48116.58418.74319.35520.14620.92520.64122.23422.72121.75320.21221.11719.85320.63619.71919.52918.43720.61821.20520.59222.39523.07924.21624.84523.75623.48524.32122.89823.22322.04321.05820.129

13.13212.73711.24110.78310.06711.15713.60412.93414.82615.38716.88917.51817.48714.74314.41614.50413.78012.61411.93011.65211.56311.07911.08014.86015.41115.19616.05117.14018.29018.68318.82115.35914.47215.84915.41014.50514.06013.11416.64817.40116.83817.99718.59819.19018.361

-37.519-38.984-39.154-40.487-41.194-40.814-36.920-36.983-36.359-35.747-35.574-36.856-34.685-34.389-33.623-34.137-33.016-33.522-32.476-31.186-32.644-31.508-30.622-32.362-32.924-31.198-30.290-29.794-30.791-31.010-31.401-28.972-28.332-28.533-27.426-27.781-26.519-28.509-26.596-27.074-25.430-24.604-23.942-24.895-25.638

73.8576.0679.0780.6281.2281.1871.0769.7568.2766.2267.0369.0166.8763.5562.5262.0160.4160.0964.2665.4066.4666.7765.7458.5057.9556.7556.2957.2459.2060.9961.3354.7854.6052.1249.1849.1047.6747.6248.0048.1546.0246.9745.6547.4246.46

RRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRR

CCCCOOCONCCOCCONCCCCNCNCONCCCONCONCCCCCONCCCC

CD2CE1CE2CZCONCACBCGCD1CE1CD2CE2CZOHCONCACBCG1CG2CONCACBCGCDOE1NE2CONCACBCONCACBCON

PHE RPHE RPHE RPHE RPHE RPHE RTYR RTYR RTYR RTYR RTYR RTYR RTYR RTYR RTYR RTYR RTYR RTYR RVAL RVAL RVAL RVAL RVAL RVAL RVAL RGLN RGLN RGLN RGLN RGLN RGLN RGLN RGLN RGLN RGLU RGLU RGLU RGLU RGLU RALA RALA RALA RALA RALA RLYS R

275275275275275275276276276276276276276276276276276276277277277277277277277278278278278278278278278278279279279279279280280280280280281

21.16219.17820.31619.24524.08023.80425.20526.13227.55628.68729.18030.35629.21830.25530.78031.86825.88026.05625.49025.05123.45822.64022.96525.75125.86226.33327.08128.21028.68030.27831.06230.68226.26426.52225.16024.33324.46922.90522.31822.34520.98620.99520.17719.63420.159

20.50818.93121.05720.32017.48916.46218.12017.89218.11317.89618.90918.59216.66916.32217.25216.86218.90220.04918.39519.28019.28418.56919.09119.14218.02620.22320.21621.08221.29221.64621.60122.00020.45520.01321.10221.64123.15221.25421.60120.44020.03018.52720.25319.32721.537

-25.191-26.577-26.240-26.842-23.421-22.790-23.289-22.206-22.781-21.890-21.024-20.072-21.773-20.863-19.988-19.341-21.133-21.242-19.987-18.964-18.838-19.923-17.483-17.613-17.077-17.123-15.792-15.824-17.239-17.406-16.435-18.645-14.545-13.532-14.739-13.721-13.731-14.034-15.055-13.145-13.386-13.699-12.142-11.575-11.689

46.2146.2745.9046.3748.1147.9048.1149.4151.0052.0053.8254.2952.5353.1154.2456.1349.4447.4251.0052.5453.0551.0252.5554.6453.3957.6460.9262.6466.6868.7269.8069.1461.7561.8863.4865.2065.0266.4066.3368.1270.5568.5172.9472.6875.96

RRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRR

CCCCCONCCCCCCCCOCONCCCCCONCCCCONCONCCCONCCCON

CACBCGCDCENZCONCACOCBSGNCACBCGCDOE1OE2CONCACBCONCDCACBCGCONCACBCGCDOE1OE2CON

LYS RLYS RLYS RLYS RLYS RLYS RLYS RLYS RCYS RCYS RCYS RCYS RCYS RCYS RGLU RGLU RGLU RGLU RGLU RGLU RGLU RGLU RGLU RASN RASN RASN RASN RASN RPRO RPRO RPRO RPRO RPRO RPRO RPRO RGLU RGLU RGLU RGLU RGLU RGLU RGLU RGLU RGLU RPHE R

281281281281281281281281282282282282282282283283283283283283283283283284284284284284285285285285285285285286286286286286286286286286287

19.41819.81619.89720.94522.36123.26617.92317.29017.33815.93015.07414.28715.47314.70815.26514.56714.60014.68313.45413.55412.40715.21916.38914.44013.14712.27913.30414.15812.39612.41211.26710.54711.13910.27510.3149.3538.5468.2089.3989.0438.0239.8917.2976.5797.049

21.81223.16023.02523.93723.38924.50221.71922.45420.71020.56321.63321.36719.18318.20822.88623.94323.58124.81425.66026.87225.09325.31925.53126.26625.89927.15825.29124.45225.70725.48426.54326.97626.21325.84224.64726.69026.37427.71528.65530.10130.54130.81725.55325.07025.396

-10.474-9.886-8.363-7.726-7.882-8.130-10.689-11.445-10.049-10.411-9.740-8.834-9.941-11.254-10.178-9.463-7.981-7.078-7.294-7.195-7.596-9.637-9.343-10.203-10.787-10.865-12.185-12.440-13.095-14.529-12.732-14.000-15.175-11.797-11.549-11.303-10.125-9.500-9.739-9.504-10.005-8.965-10.455-9.602-11.760

79.5479.8680.0179.4079.4679.4382.0881.6784.5486.7288.4989.7286.3588.4590.1192.0392.4693.7395.0795.3695.1093.0393.4294.2295.8395.7997.3698.0098.2498.8699.1698.5498.6799.8999.92100.79102.10103.19106.31109.22110.82109.63101.95102.44101.53

RRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRR

CCCCCNCONCCOCSNCCCCOOCONCCCONCCCCCONCCCCOOCON

CACBCGCD1CD2CE1CE2CZCONCACBCGCDOE1OE2CONCACBCONCACBOG1CG2CONCACBOGCONCACOCBSGNCA

PHE RPHE RPHE RPHE RPHE RPHE RPHE RPHE RPHE RPHE RGLU RGLU RGLU RGLU RGLU RGLU RGLU RGLU RGLU RASN RASN RASN RASN RASN RTHR RTHR RTHR RTHR RTHR RTHR RTHR RSER RSER RSER RSER RSER RSER RCYS RCYS RCYS RCYS RCYS RCYS RPHE RPHE R

287287287287287287287287287287288288288288288288288288288293293293293293294294294294294294294295295295295295295296296296296296296297297

6.0176.2465.5195.0835.4074.5544.8774.4536.2315.6627.0717.5598.3648.2887.1896.4187.1148.4758.80615.77616.67816.08216.84817.58416.05915.79414.28413.61713.87416.59617.32916.50217.29718.67119.14116.64315.92616.88516.28116.93917.74614.79314.48716.58317.301

24.44124.16625.18426.32425.07327.37926.13527.29623.10622.76822.34621.01820.60821.66321.29620.38321.93920.99021.99913.98813.05611.65513.40012.78814.40314.56414.78713.71914.83715.68216.46115.68016.61115.96815.52916.78015.90017.96418.16819.32120.07118.46719.49419.32720.129

-12.168-13.655-14.443-13.787-15.813-14.516-16.534-15.891-11.495-10.455-12.238-11.927-13.169-14.287-15.253-14.968-16.289-10.695-10.105-4.556-5.247-5.105-6.723-7.497-7.132-8.540-8.711-8.060-10.198-9.162-8.558-10.483-11.209-11.391-10.111-12.538-12.998-13.112-14.431-15.191-14.657-14.245-12.793-16.478-17.437

101.39100.97100.24100.2799.82100.4299.7999.91101.27101.94100.0298.6198.3696.7996.2395.7495.8298.2899.0996.3094.1994.1793.1693.0691.2189.2989.6090.2589.4787.9888.2485.9083.5383.7783.5381.7281.1780.5579.6577.1176.8782.5587.3074.6872.94

RRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRR

CCCCCCCCCONCCCCOOCONCCCONCCOCCONCCOCONCCOCSNC

CBCGCD1CD2CE1CE2CZCONCACBCGSDCECONCACBCG1CG2CONCDCACBCGCONCACONCACBCG1CG2CONCACB

PHE RPHE RPHE RPHE RPHE RPHE RPHE RPHE RPHE RMET RMET RMET RMET RMET RMET RMET RMET RVAL RVAL RVAL RVAL RVAL RVAL RVAL RPRO RPRO RPRO RPRO RPRO RPRO RPRO RGLY RGLY RGLY RGLY RVAL RVAL RVAL RVAL RVAL RVAL RVAL RLEU RLEU RLEU R

297297297297297297297297297298298298298298298298298299299299299299299299300300300300300300300301301301301302302302302302302302303303303

18.46318.95419.63418.66320.02819.06119.74216.37015.77616.19715.24414.80913.35112.23810.79815.85016.83515.24315.68215.27415.62115.96914.98413.75415.76617.23115.18216.21117.58414.78815.43913.65313.33012.45212.76211.34010.33610.53010.25312.0098.9058.7177.8826.5916.528

19.26619.78120.98819.09421.51419.62520.83620.48219.62121.80222.23123.66023.73624.19123.26522.18622.84021.34021.26319.89619.79418.78822.33222.36223.25623.36724.33825.44524.88523.87223.06224.36924.15722.92322.10522.80321.80220.71919.32320.74422.36523.56121.46221.53820.691

-17.930-19.242-19.284-20.408-20.507-21.633-21.686-18.598-19.241-18.807-19.825-19.491-19.032-20.368-19.817-21.235-21.542-22.087-23.476-24.016-25.502-23.253-24.307-24.417-24.877-24.920-25.621-25.714-25.326-27.029-27.659-27.508-28.925-29.217-30.061-28.482-28.727-27.697-28.323-27.282-28.811-29.002-28.616-29.421-30.692

69.4766.1564.5265.0963.4964.9863.8873.4173.8074.3674.9878.0781.7587.0885.8173.5772.2373.6274.4374.2773.2173.3575.4176.0076.1075.6576.8575.8476.4877.7277.1879.0380.4082.2882.0783.9586.2485.5184.8384.4787.9788.6890.0391.4792.45

RRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRR

CCCCCCCCONCCCSCCONCCCCCONCCCCCONCCONCCCCCONCC

CGCD1CD2CONCDCACBCGCONCACBCONCACBCONCACBCGCD1CD2CONCACBCGOD1ND2CONCACBOG1CG2CO

LEU RLEU RLEU RLEU RLEU RPRO RPRO RPRO RPRO RPRO RPRO RPRO RASP RASP RASP RASP RASP RTHR RTHR RTHR RTHR RTHR RLEU RLEU RLEU RLEU RLEU RLEU RLEU RLEU RASN RASN RASN RASN RASN RASN RASN RASN RTHR RTHR RTHR RTHR RTHR RTHR RTHR R

303303303303303304304304304304304304305305305305305306306306306306307307307307307307307307308308308308308308308308309309309309309309309

7.9137.9258.4375.1615.0094.1172.7014.2432.9731.8654.2803.3085.4015.4656.4336.2867.4206.0206.8616.1206.5366.1446.6477.6707.8617.9117.0577.4789.0249.8029.24110.60410.76410.58411.5249.33010.83710.10111.94312.47412.80111.54813.20213.70914.518

20.42119.13021.51821.81622.83220.90821.19119.45819.08720.02418.54217.89818.53218.03418.86716.78916.62316.04415.10715.10414.11014.64212.74012.04510.8859.7279.9468.45412.79512.91013.11013.19814.55315.66616.08616.14512.03911.85511.33510.3619.1208.6098.07410.82111.399

-31.277-32.088-32.194-28.787-28.151-28.913-29.072-28.646-27.857-28.339-29.935-30.245-30.664-32.072-32.899-32.066-32.600-30.999-30.538-29.244-31.632-32.721-31.554-30.710-31.609-30.735-29.505-31.417-30.662-31.602-29.379-28.882-28.180-29.187-29.860-29.307-27.921-26.960-28.154-27.219-27.933-28.443-26.978-26.516-27.106

93.4693.4693.7992.3692.5892.7793.5292.9292.9193.4292.8492.3692.5091.7192.0190.8791.2289.2587.1687.7985.6886.7383.4681.3883.3384.5085.3784.8578.7277.7674.8770.8871.0571.3269.4272.7667.3266.3363.6860.5761.5461.7960.4157.3156.57

RRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRR

CCCCONCCCCCONCCCONCCCONCCCCCCONCCCONCONCCOCCO

NCACBCG1CG2CONCACBCGCDNECZNH1NH2CONCACBCG2CG1CD1CONCACBCGCDNECZNH1NH2CONCACBCG1CG2CON

VAL RVAL RVAL RVAL RVAL RVAL RVAL RARG RARG RARG RARG RARG RARG RARG RARG RARG RARG RARG RILE RILE RILE RILE RILE RILE RILE RILE RARG RARG RARG RARG RARG RARG RARG RARG RARG RARG RARG RVAL RVAL RVAL RVAL RVAL RVAL RVAL RLYS R

310310310310310310310311311311311311311311311311311311312312312312312312312312313313313313313313313313313313313314314314314314314314315

13.71914.81114.65013.41015.64415.49814.83216.84417.63618.38217.46618.22519.16420.09420.28620.93018.63819.16019.00520.05419.42520.43718.33517.55221.13020.81222.39723.45524.44325.12025.77026.64127.61527.78028.44024.21624.10125.22125.78324.86725.56123.64427.21327.54928.012

10.66210.97212.23612.69112.4789.8548.9659.8819.0448.0717.1315.9516.4495.6864.4836.1839.87310.8499.39710.00910.76011.52611.63012.1969.1048.0759.4858.7618.1148.9948.1538.9678.4677.2239.2119.67510.9269.1589.9299.5399.40010.4749.4958.41010.410

-25.207-24.379-23.544-23.283-22.538-23.760-23.452-23.680-22.827-23.685-24.231-24.887-25.845-26.333-25.817-27.166-22.106-22.564-20.972-20.194-18.938-18.285-19.384-18.148-19.668-19.145-19.792-19.035-20.054-20.854-22.104-22.942-23.644-23.634-24.327-18.156-18.315-17.462-16.364-15.130-13.942-15.035-16.103-16.273-15.597

54.4752.3851.8252.4147.6752.0051.0650.3950.3449.7750.3348.2548.4047.7747.0144.8650.0550.0149.2748.5848.1545.6247.0747.9147.9048.7746.5746.0645.9543.8545.6447.5148.5248.9348.7246.3544.3745.2945.7446.1347.4844.8745.8645.1945.17

RRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRR

NCCCCCONCCCCNCNNCONCCCCCCONCCCCNCNNCONCCCCCON

CACBCGCDCENZCONCACBOG1CG2CONCACBCGOD1ND2CONCACBCGCDCENZCONCACBCGCD1CD2CONCACOCB

LYS RLYS RLYS RLYS RLYS RLYS RLYS RLYS RTHR RTHR RTHR RTHR RTHR RTHR RTHR RASN RASN RASN RASN RASN RASN RASN RASN RLYS RLYS RLYS RLYS RLYS RLYS RLYS RLYS RLYS RLEU RLEU RLEU RLEU RLEU RLEU RLEU RLEU RCYS RCYS RCYS RCYS RCYS R

315315315315315315315315316316316316316316316317317317317317317317317318318318318318318318318318319319319319319319319319320320320320320

29.41130.39630.50031.60131.72432.77829.86029.23930.99331.39932.39433.36231.76732.11032.80331.87332.66132.12331.13231.22730.17034.13634.33534.94536.30137.30337.00138.02837.33238.02736.31937.35735.11834.97933.81533.84232.54934.94534.82635.15334.25534.14335.10035.79332.670

10.18610.45311.87112.11713.60013.95710.91511.84410.56311.33710.58710.1779.35512.60612.50613.81614.99716.01316.67816.78017.16414.78613.89915.79915.93516.66618.22319.02019.97321.27916.58316.47716.83617.46918.46819.32120.10920.36216.48816.82615.28014.28713.11112.59413.787

-15.205-16.373-16.660-17.811-18.055-19.216-14.049-13.662-13.451-12.235-11.331-12.194-10.816-12.705-13.640-12.092-12.130-10.778-11.276-12.543-10.603-11.786-11.074-11.916-11.309-12.338-12.395-13.178-14.178-14.250-9.871-9.205-9.312-8.010-8.032-9.298-9.435-9.298-6.821-5.671-7.087-6.015-6.283-5.408-5.987

45.6045.3647.2847.5448.2047.7044.2745.2743.4742.8342.2642.0940.8843.1041.1143.5246.3846.5650.6654.7551.2947.7247.4648.9050.2252.0254.6656.6960.3762.5249.3647.9349.1450.7649.5249.5051.1449.0851.6652.1052.9154.2754.3854.3554.57

RRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRR

CCCCCNCONCCOCCONCCCONCONCCCCCNCONCCCCCCONCCOC

SGNCACBCGCD1CE1CD2CE2CZOHCONCACBCGCDOE1OE2CONCACBCGOD1OD2CONCACBCGOD1OD2CONCACBCGCDCENZ

CYS RTYR RTYR RTYR RTYR RTYR RTYR RTYR RTYR RTYR RTYR RTYR RTYR RGLU RGLU RGLU RGLU RGLU RGLU RGLU RGLU RGLU RASP RASP RASP RASP RASP RASP RASP RASP RASP RASP RASP RASP RASP RASP RASP RASP RLYS RLYS RLYS RLYS RLYS RLYS RLYS R

320321321321321321321321321321321321321322322322322322322322322322323323323323323323323323324324324324324324324324325325325325325325325

31.44435.05235.92135.03834.10934.55633.70332.77931.94032.37731.56036.86937.60536.78037.58338.79639.98341.27242.16741.37136.75435.91636.94436.25936.04335.39035.22835.08637.13937.94736.75337.33237.44738.40439.61437.94436.55436.89135.50234.62235.38236.26236.85837.80037.884

15.09412.64711.56610.4379.8358.8808.42410.2719.8318.9108.53612.12813.09511.53012.04911.12811.69811.32110.86611.49711.97811.10512.97012.86414.27714.30813.26115.40912.05312.56710.8139.7958.4338.5408.8288.4059.6668.85510.48310.26010.51711.76112.02913.23013.752

-5.670-7.540-7.924-8.520-7.496-6.570-5.563-7.435-6.417-5.496-4.446-8.981-8.757-10.162-11.231-11.294-12.070-11.396-12.082-10.186-12.512-12.684-13.403-14.685-15.247-16.635-17.257-17.097-15.616-16.354-15.617-16.458-15.700-14.456-14.657-13.275-17.764-18.629-17.906-19.064-20.361-20.325-21.703-21.724-23.087

55.6755.4457.4957.6257.7958.2558.5457.0858.2258.8760.5958.7059.3260.7362.4164.0870.3474.5077.2176.9061.9961.3262.1961.6161.3462.5461.2362.9260.9061.7559.0959.5458.1858.1255.6557.0059.6959.3759.3858.8059.6363.3765.7968.0670.49

RRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRR

SNCCCCCCCCOCONCCCCOOCONCCCOOCONCCCOOCONCCCCCN

CONCACBCGCD1CD2CONCACBCGCD2CE2CE3CD1NE1CZ2CZ3CH2CONCACBOGCONCACBCGOD1ND2CONCACBCGCD2CE2CE3

LYS RLYS RLEU RLEU RLEU RLEU RLEU RLEU RLEU RLEU RTRP RTRP RTRP RTRP RTRP RTRP RTRP RTRP RTRP RTRP RTRP RTRP RTRP RTRP RSER RSER RSER RSER RSER RSER RASN RASN RASN RASN RASN RASN RASN RASN RTRP RTRP RTRP RTRP RTRP RTRP RTRP R

325325326326326326326326326326327327327327327327327327327327327327327327328328328328328328329329329329329329329329330330330330330330330

34.08733.97233.80333.31933.98634.49534.87933.46231.80831.28131.10229.65429.14829.59629.04229.66428.08730.54030.61629.32927.74728.37528.98229.46027.84426.99525.93024.98326.32626.38825.71224.87024.26725.34726.34325.12623.74323.35223.24022.08621.71122.68822.78423.79922.123

8.8398.1988.3316.9716.3524.9324.2134.0496.9927.0457.0127.1447.4668.80810.06811.08810.4239.10710.43512.41511.74712.7525.8594.7466.0414.8895.2966.1654.4645.1553.2672.8941.5230.4760.615-0.6133.9154.6054.0324.8934.8515.6217.0647.3488.119

-19.095-20.135-17.897-17.802-16.573-16.818-15.523-17.512-17.637-16.536-18.793-18.732-20.138-20.562-20.137-20.904-19.188-21.567-21.836-20.704-18.988-19.752-18.245-18.442-17.554-17.304-16.287-16.912-18.609-19.623-18.579-19.704-19.395-19.454-20.156-18.698-19.869-18.938-21.113-21.323-22.808-23.615-23.719-24.670-23.095

57.1558.6955.1652.1054.7955.9757.6254.3850.0948.9647.7247.2444.7042.5140.9040.2838.8538.5639.5238.7438.3239.2648.4048.7048.5049.0546.8246.9649.9250.2249.2348.8849.1650.8451.9649.4448.9548.3948.8048.8848.2347.2347.2246.2946.83

RRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRR

CONCCCCCCONCCCCCCCNCCCCONCCOCONCCCONCONCCCCCC

CD1NE1CZ2CZ3CH2CONCACBOGCONCACBCGCDOE1NE2CONCACBCGCDOE1OE2CONCACBCGSDCECONCACBOGCO

TRP RTRP RTRP RTRP RTRP RTRP RTRP RSER RSER RSER RSER RSER RSER RGLN RGLN RGLN RGLN RGLN RGLN RGLN RGLN RGLN RGLU RGLU RGLU RGLU RGLU RGLU RGLU RGLU RGLU RMET RMET RMET RMET RMET RMET RMET RMET RSER RSER RSER RSER RSER RSER R

330330330330330330330331331331331331331332332332332332332332332332333333333333333333333333333334334334334334334334334335335335335335335

23.64524.33324.11622.44023.44820.90220.67420.15218.92818.32417.73917.93518.12616.86315.76914.79615.42815.63814.71716.93515.07115.11314.45413.90613.84213.44713.52712.58914.54912.53111.87412.14610.78010.6729.3929.0999.26610.41311.2009.2628.8358.6558.5147.6237.164

5.0916.0588.6629.4339.7044.4143.2245.3784.9976.2627.0524.3924.4133.7973.4102.5471.2270.339-0.1520.1324.6645.7284.5395.7435.5824.1754.0974.5233.6376.0975.3397.3407.7648.3759.1959.6518.0128.8039.6788.7489.7199.1307.77810.53210.355

-24.508-25.170-24.973-23.398-24.340-20.481-20.306-19.917-19.225-18.613-19.650-20.213-21.421-19.663-20.539-19.739-19.293-20.497-21.127-20.801-21.056-20.452-22.238-22.834-24.354-24.795-26.303-26.962-26.810-22.286-21.585-22.587-22.370-20.973-20.797-19.083-18.359-23.418-23.756-24.104-25.151-26.526-26.432-24.740-23.583

47.2947.4245.4446.7344.8948.6550.5549.5650.7849.1547.9853.5154.3855.7058.5459.2363.5866.0368.6166.3958.9258.5959.7461.0560.9063.1864.9565.0765.8561.4162.1061.9063.0863.0163.1765.1662.3663.7663.5864.9166.2066.2368.3167.1466.71

RRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRR

CNCCCCONCCOCONCCCCONCONCCCCOOCONCCCSCCONCCOCO

NCACBCG2CG1CD1CONCACONCACBCGCDCENZCONCACBCOOXTCBCGOD1OD2CONCANCACBCG2CG1CD1CONCA

ILE RILE RILE RILE RILE RILE RILE RILE RGLY RGLY RGLY RGLY RLYS RLYS RLYS RLYS RLYS RLYS RLYS RLYS RLYS RLYS RLYS RLYS RLYS RLYS RLYS RASP LASP LASP LASP LASP LASP LASP LASP LILE LILE LILE LILE LILE LILE LILE LILE LVAL LVAL L

336336336336336336336336337337337337338338338338338338338338338339339339339339339111111112222222233

7.2846.2346.6667.7335.4855.7815.8356.6904.5743.9063.5823.7713.0802.9401.7722.1242.4632.6143.8303.0123.0533.2442.9893.6083.6874.9482.96645.10843.77243.68442.73947.51648.11445.98946.14848.03549.27349.73150.96650.07550.60049.16148.21650.04850.093

11.53012.51413.69614.61914.60915.76513.14213.23113.59714.09312.99111.83013.34812.39011.3919.9538.7097.3497.10812.88314.07811.86011.51412.48710.0649.7299.03147.53647.24846.20647.83347.07147.86346.82346.65846.57947.06946.11146.53444.84843.74348.48648.80649.37450.795

-25.565-25.362-24.423-25.063-24.079-23.018-26.728-27.607-26.834-28.019-28.991-28.623-30.199-31.351-31.148-31.819-30.943-31.841-32.718-32.821-33.092-33.664-35.098-36.108-35.124-35.171-34.89419.26319.77720.48619.39019.38019.92021.35319.90318.24917.76316.74615.91917.38816.27117.26416.49217.74117.349

68.3770.6970.0669.3469.8969.8073.1073.3775.3077.9880.7080.9183.7386.4087.1888.1889.2090.0590.0787.9288.3289.4390.6690.6591.5992.2392.6855.2857.0758.5958.0353.8853.8054.3953.8553.0251.4651.8950.8651.8652.3550.8752.2949.9947.23

RRRRRRRRRRRRRRRRRRRRRRRRRRRLLLLLLLLLLLLLLLLLL

NCCCCCCONCCONCCCCCNCONCCCOOCCOOCONCNCCCCCCONC

CBCG1CG2CONCACBCGCD1CD2CONCACBOG1CG2CONCACBCGCDOE1NE2CONCACBOGCONCDCACBCGCONCACB

VAL LVAL LVAL LVAL LVAL LLEU LLEU LLEU LLEU LLEU LLEU LLEU LLEU LTHR LTHR LTHR LTHR LTHR LTHR LTHR LGLN LGLN LGLN LGLN LGLN LGLN LGLN LGLN LGLN LSER LSER LSER LSER LSER LSER LPRO LPRO LPRO LPRO LPRO LPRO LPRO LALA LALA LALA L

333334444444455555556666666667777778888888999

50.38550.54349.24351.28852.28851.11552.17751.79451.20550.96652.11152.37851.51453.59554.02354.81253.83155.15954.84655.91554.39555.27154.33453.37752.67851.52753.31156.16455.83457.36058.13659.13959.81058.93159.21159.20859.79058.76359.46559.46957.27256.76156.62455.19954.666

51.69353.21951.54150.93450.41151.54951.74051.27349.85349.67348.79253.27153.99553.66555.00655.19954.99356.61555.32154.89356.19056.49756.78755.56655.62255.13856.19657.68458.70857.61358.88158.83657.74758.98457.95260.15760.40961.39462.42961.92161.52860.74462.57862.81763.799

18.56418.19219.55116.43916.71915.30614.34212.80112.68311.41413.31014.30614.01014.40414.37315.70516.77015.83513.12313.00712.24911.0519.8689.5848.3998.4427.28511.33212.13810.80310.86911.99012.0829.5679.1219.0017.6829.5828.7807.4289.3998.6599.9239.69210.774

45.7240.7544.6146.8747.4445.4746.5146.3747.8747.1747.0945.9245.6245.9546.8546.6547.0745.7646.1947.9445.3044.8444.6542.7743.2640.7240.3144.6044.6244.4044.6445.0243.1044.1643.0744.1842.5544.9545.5443.8246.3345.8446.6747.3144.86

LLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLL

CCCCONCCCCCCONCCOCCONCCCCONCONCCOCONCCCCCONCC

CONCACBOGCONCACBCGCD1CD2CONCACBCONCACBCG1CG2CONCACBOGCONCACBCGCD1CD2CONCAC

ALA LALA LSER LSER LSER LSER LSER LSER LLEU LLEU LLEU LLEU LLEU LLEU LLEU LLEU LALA LALA LALA LALA LALA LVAL LVAL LVAL LVAL LVAL LVAL LVAL LSER LSER LSER LSER LSER LSER LLEU LLEU LLEU LLEU LLEU LLEU LLEU LLEU LGLY LGLY LGLY L

9910101010101011111111111111111212121212131313131313131414141414141515151515151515161616

54.99753.99455.95455.86555.18855.94057.24958.22057.43658.69659.67759.45558.22360.62758.58257.62859.59059.68259.62461.03862.06961.01962.09661.86763.09061.88162.08160.96563.26663.37264.66465.03463.19663.39562.69862.57462.14260.71659.91160.00563.91464.93063.79564.82265.683

63.49463.26964.25664.85766.12467.00565.12665.19965.11665.34964.27362.84262.74562.24265.89065.51566.69567.38868.83966.95166.97366.49965.90264.41763.70063.65066.38766.53266.55267.11267.79868.80966.05864.85966.43465.39066.02466.50167.28965.20464.65465.28963.33762.28461.943

8.2917.6377.8506.3966.3777.1535.8936.7134.5564.0514.1743.6813.0642.8682.6642.0262.2550.9261.1080.3531.136-0.936-1.610-1.751-2.535-0.385-3.096-3.673-3.698-5.090-5.413-4.530-6.019-5.695-7.134-8.237-9.524-9.429-10.574-9.238-8.459-8.375-8.663-8.802-7.633

47.6547.2447.3947.2747.8652.4246.2445.5745.5547.0246.1948.7348.2947.0447.8049.0548.6749.1847.8649.7350.0349.6949.5650.1049.0348.4949.8148.9051.0852.5953.6457.5452.1950.2053.2754.5355.4058.5658.0160.2755.5555.3656.7558.6360.16

LLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLL

CONCCOCONCCCCCCONCCCONCCCCCONCCOCONCCCCCCONCC

ONCACBCGCDOE1NE2CONCACBCGCDNECZNH1NH2CONCACBCONCACBOG1CG2CONCACBCG2CG1CD1CONCACBOG

GLY LGLN LGLN LGLN LGLN LGLN LGLN LGLN LGLN LGLN LARG LARG LARG LARG LARG LARG LARG LARG LARG LARG LARG LALA LALA LALA LALA LALA LTHR LTHR LTHR LTHR LTHR LTHR LTHR LILE LILE LILE LILE LILE LILE LILE LILE LSER LSER LSER LSER L

161717171717171717171818181818181818181818191919191920202020202020212121212121212122222222

66.67465.43465.96365.97866.93168.41969.14868.78765.17364.23965.61865.17966.35665.97567.13967.63368.20068.37668.59764.42364.87863.28562.59761.26162.47362.18162.55362.53063.97664.81163.99761.48861.49560.59459.47858.26757.10158.19956.82859.55059.65459.50059.53060.87061.230

61.25362.60762.21763.45564.63564.08963.56764.10861.03660.49860.65959.48558.69757.34156.52057.42257.06755.78158.02759.82760.59759.22559.39859.87858.12057.05758.23057.14556.98456.24755.98257.30158.25056.35356.57156.53156.52257.82957.89355.39354.24555.60454.45554.31955.479

-7.795-6.519-5.216-4.328-4.734-5.008-4.073-6.313-4.565-5.052-3.379-2.698-2.216-1.777-1.168-0.1550.9311.2101.771-1.432-0.565-1.304-0.115-0.4650.563-0.0831.8612.7293.3202.3494.4503.9654.6624.1845.1384.3325.2293.5132.6646.1025.5887.4128.2188.7539.171

61.7160.6160.8661.9863.1665.1765.1664.5560.5660.1860.2260.5462.3366.7768.4271.6573.0474.4273.5259.7359.9557.6656.9756.4156.0155.9054.5754.7155.3158.5254.1554.2355.0152.5551.3951.0350.7250.6251.3850.8950.7548.7249.2850.7954.83

LLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLL

ONCCCCONCONCCCCNCNNCONCCCONCCOCCONCCCCCCONCCO

CONCACOCBSGNCACBCGCDCENZCONCACBCONCACBOGCONCACBCGCDOE1OE2CONCACBOGCONCA

SER LSER LCYS LCYS LCYS LCYS LCYS LCYS LLYS LLYS LLYS LLYS LLYS LLYS LLYS LLYS LLYS LALA LALA LALA LALA LALA LSER LSER LSER LSER LSER LSER LGLU LGLU LGLU LGLU LGLU LGLU LGLU LGLU LGLU LSER LSER LSER LSER LSER LSER LVAL LVAL L

222223232323232324242424242424242425252525252626262626262727272727272727272828282828282929

58.39557.51958.28057.21757.81158.42056.23054.57657.26157.58358.39158.42959.89760.18261.60256.40255.43556.37655.23454.95355.44556.48054.39854.56753.33252.24354.77455.01354.63754.83853.45353.15352.82451.60753.79355.19154.88455.71556.16156.72357.52955.00054.12455.16254.170

54.15355.01752.94352.63451.94650.96251.64851.05652.21051.32352.15851.72651.57750.18849.67950.79551.45449.57249.02847.72448.69448.26748.74048.56749.10548.43547.17546.92346.24344.86144.33443.58244.53144.91444.89344.23344.73143.02742.38241.07740.53542.10041.63042.20741.736

9.1399.4849.51610.43711.66711.5689.69610.34212.74214.01214.92216.59316.95417.67517.49914.61914.98014.89215.54614.76217.02217.39917.79719.24219.92019.29219.63220.72118.72918.92819.15320.42921.58521.71022.33417.62416.61217.63116.35116.65615.62215.48115.97714.14113.189

48.6148.6148.0949.4049.1750.5547.9852.9548.8549.7650.7252.1955.3656.9258.5349.3149.1649.3049.4847.9650.2049.4451.0853.1352.2852.6555.4055.8656.9657.5260.8966.0370.4573.0272.0256.3354.8656.6755.2753.9656.4954.4354.1253.9953.99

LLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLL

CONCCOCSNCCCCCNCONCCCONCCOCONCCCCOOCONCCOCONC

CBCG1CG2CONCACBCGOD1OD2CONCACBCGOD1ND2CONCACBCGCD1CE1CD2CE2CZOHCONCACONCACBCGCDCENZC

VAL LVAL LVAL LVAL LVAL LASP LASP LASP LASP LASP LASP LASP LASP LASN LASN LASN LASN LASN LASN LASN LASN LTYR LTYR LTYR LTYR LTYR LTYR LTYR LTYR LTYR LTYR LTYR LTYR LGLY LGLY LGLY LGLY LLYS LLYS LLYS LLYS LLYS LLYS LLYS LLYS L

292929292930A30A30A30A30A30A30A30A30B30B30B30B30B30B30B30B30C30C30C30C30C30C30C30C30C30C30C30C30D30D30D30D30E30E30E30E30E30E30E30E

53.76053.45054.79454.68454.02955.82356.20757.61058.54059.70958.26255.44155.03255.17254.37653.12252.33852.06252.05155.19755.54955.97256.96656.39355.80456.57556.06254.51653.99454.75154.17758.01457.97958.70759.59558.97459.69657.65557.22156.28256.49955.68056.23855.91756.619

42.90544.03043.33240.56740.12839.96438.72438.43739.37639.19240.29737.45337.34436.56135.29035.26333.97833.58133.23134.01833.29933.85132.72831.31830.43329.52128.86830.53029.93429.05728.33132.88632.19733.97834.46835.38635.90535.57436.52135.89334.50833.33332.00030.96537.756

12.24613.13111.21612.44911.56512.80912.09712.30711.58511.91510.70612.54813.69211.63711.87411.10211.31012.46110.11911.81012.90710.82611.25510.87111.99712.65113.66312.33513.35914.04315.16110.3229.22110.5169.4518.4297.5948.4257.3956.2225.7416.7606.7997.7808.105

52.0750.6150.8155.4355.8055.8556.2457.4060.9563.2260.7655.4454.1156.0156.7557.1957.9756.4056.2657.6359.3858.1257.5659.5962.3863.9865.3762.7365.3166.2867.5356.7856.5255.1853.8453.1052.9852.4451.9653.5452.8652.4453.2152.6850.72

LLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLL

CCCCONCCCOOCONCCCONCONCCCCCCCCOCONCCONCCCCCNC

ONCACBOGCONCACBCGCD1CD2CONCACBCGSDCECONCACBCGCD2ND1CE1NE2CONCACBCGCD2CE2CE3CD1NE1CZ2CZ3CH2

LYS LSER LSER LSER LSER LSER LSER LLEU LLEU LLEU LLEU LLEU LLEU LLEU LLEU LMET LMET LMET LMET LMET LMET LMET LMET LHIS LHIS LHIS LHIS LHIS LHIS LHIS LHIS LHIS LHIS LTRP LTRP LTRP LTRP LTRP LTRP LTRP LTRP LTRP LTRP LTRP LTRP L

30E3131313131313232323232323232333333333333333334343434343434343434353535353535353535353535

56.01056.79556.36857.40858.77655.07355.00754.08252.70751.65851.95150.94352.06352.49451.62053.13553.11454.45354.70653.56554.23452.97853.59952.11351.93050.51450.19049.21750.83850.29749.30451.89051.72252.11752.20253.55954.52554.94456.05254.49155.57356.43956.70455.08256.169

37.57638.95540.15841.26540.78640.59640.93140.73240.89040.12638.63537.80138.08442.42142.80043.18244.62945.21246.72347.47647.18844.92444.26945.87546.32145.88844.50544.04743.40042.33042.71147.79848.48848.37049.81550.14250.10851.22450.76052.50249.17049.54851.59253.33252.825

9.0967.6028.3088.1948.4897.6756.4968.5428.0428.9599.0789.7427.5888.1288.8617.2157.1957.6367.3478.81610.4305.6554.7805.3323.9103.6334.0494.8643.5744.1404.9073.8594.9232.6762.4812.0253.1723.9714.8004.1653.3064.3005.7365.3096.002

51.3147.5746.8547.1349.9446.3047.1545.5444.9543.4542.4440.4340.3545.9045.9644.6846.6248.4051.5357.6055.2745.9045.8043.8043.2742.7041.6544.2142.7643.5042.7942.8144.2341.8441.5740.4641.3541.7341.6840.1041.3441.8341.4541.1141.44

LLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLL

ONCCOCONCCCCCCONCCCSCCONCCCCNCNCONCCCCCCCNCCC

CONCACBCGCD1CE1CD2CE2CZOHCONCACBCGCDOE1NE2CONCACBCGCDOE1NE2CONCACBCGCDCENZCONCDCACB

TRP LTRP LTYR LTYR LTYR LTYR LTYR LTYR LTYR LTYR LTYR LTYR LTYR LTYR LGLN LGLN LGLN LGLN LGLN LGLN LGLN LGLN LGLN LGLN LGLN LGLN LGLN LGLN LGLN LGLN LGLN LGLN LLYS LLYS LLYS LLYS LLYS LLYS LLYS LLYS LLYS LPRO LPRO LPRO LPRO L

353536363636363636363636363637373737373737373738383838383838383839393939393939393940404040

51.21051.01250.48949.54848.06847.63348.01847.72847.00546.66247.07046.78249.88350.50949.53549.70450.18650.49451.02450.37752.18048.32447.49748.03146.76745.98944.57043.66144.15342.27547.13247.43347.00347.00047.07948.10448.62748.30449.53445.82044.81145.96747.11944.89245.487

50.27949.56751.38451.88151.82350.52450.09948.72149.64748.28447.85046.54453.40054.08653.81855.15855.13356.43156.48456.06657.01355.76555.06456.96257.64457.80358.43358.45158.58458.20559.05759.96259.22960.50260.35459.37059.50858.42658.01261.32460.78262.65163.38763.54864.858

1.4570.3721.7250.7691.2981.8723.0403.4381.0201.4262.6513.0430.5091.359-0.725-1.255-2.658-3.274-4.754-5.645-4.930-1.490-2.111-0.927-1.2000.033-0.1901.0682.1910.809-1.704-0.961-2.988-3.632-5.121-5.531-6.952-7.919-8.719-3.269-2.807-3.375-3.934-3.036-3.472

42.2343.5340.0639.5838.1039.6537.4737.5236.9236.8737.7539.2940.3138.6639.9640.8339.7942.0744.5047.3643.4540.8839.8241.6342.5042.2641.9642.4240.9241.0343.4843.7545.1646.8848.0950.0753.5256.2556.2447.8647.1748.2348.7848.3849.68

LLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLL

CONCCCCCCCCOCONCCCCONCONCCCCONCONCCCCCNCONCCC

CGCONCACONCACBCGCDOE1NE2CONCACBOGCONCDCACBCGCONCACBCGCDCENZCONCACBCGCD1CD2C

PRO LPRO LPRO LGLY LGLY LGLY LGLY LGLN LGLN LGLN LGLN LGLN LGLN LGLN LGLN LGLN LSER LSER LSER LSER LSER LSER LPRO LPRO LPRO LPRO LPRO LPRO LPRO LLYS LLYS LLYS LLYS LLYS LLYS LLYS LLYS LLYS LLEU LLEU LLEU LLEU LLEU LLEU LLEU L

404040414141414242424242424242424343434343434444444444444445454545454545454546464646464646

46.95543.59243.60542.47241.15640.83039.76541.82441.79643.03942.94844.15044.75544.62341.76441.80841.52341.33740.20940.67942.80043.67443.11842.20044.34544.18043.08444.58643.64945.80746.23646.56047.53447.32848.38448.00747.43948.36747.43948.42047.96749.09149.24548.51949.719

64.69463.40063.32963.23962.98261.53761.19560.71659.30059.07259.65859.25660.17057.91858.31758.70757.06256.11455.25754.39355.40455.64154.82954.69554.12953.41354.30153.04852.52052.79551.81652.56651.93152.72952.37251.16751.03551.60149.78048.87147.35446.34946.38644.93648.986

-3.202-3.829-5.042-3.114-3.786-4.182-4.532-4.258-4.507-5.281-6.822-7.607-8.261-7.519-3.141-2.045-3.326-2.324-2.712-3.771-2.199-3.047-1.0390.070-0.8430.3871.176-1.945-2.368-2.306-3.267-4.574-5.593-7.044-8.178-9.072-2.780-2.208-3.087-2.462-2.414-1.995-0.548-2.299-3.187

50.1648.8548.7949.5950.0250.7150.6750.8751.7552.9155.2256.6858.2157.4450.9751.0849.3548.1150.0052.6246.7045.0746.2947.1946.3746.5247.0746.8347.1646.1947.1346.2149.7953.6155.0859.1446.1547.2745.4644.6343.9444.1841.7143.6144.28

LLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLL

CCONCCONCCCCONCONCCOCONCCCCCONCCCCCNCONCCCCCC

ONCACBCGCD1CD2CONCACBCG2CG1CD1CONCACBCGCD1CE1CD2CE2CZOHCONCACBCGCDNECZNH1NH2CONCACBCO

LEU LLEU LLEU LLEU LLEU LLEU LLEU LLEU LLEU LILE LILE LILE LILE LILE LILE LILE LILE LTYR LTYR LTYR LTYR LTYR LTYR LTYR LTYR LTYR LTYR LTYR LTYR LARG LARG LARG LARG LARG LARG LARG LARG LARG LARG LARG LALA LALA LALA LALA LALA L

464747474747474747484848484848484849494949494949494949494950505050505050505050505151515151

49.78450.82252.11752.82252.34353.21552.64552.92053.66053.02453.89355.14856.08355.89557.12353.16952.71353.06952.54451.44751.99852.30252.57451.99652.27852.56752.84153.62654.69553.31854.31854.26354.27354.34253.53653.80154.76553.03655.78056.76055.83156.99657.80658.05458.836

48.75549.18849.28950.50051.88652.80552.21748.06147.58247.70846.65947.29646.17048.10347.37545.82446.30544.52343.57542.72541.86640.53139.65642.31941.44740.12239.24642.68442.45242.21941.35639.96338.89037.48137.40336.39435.53336.22641.84441.09043.16644.06043.47844.32245.259

-4.415-2.491-3.171-2.533-2.865-1.949-4.259-2.889-3.804-1.562-1.077-0.472-0.035-1.540-2.060-0.0130.993-0.3360.646-0.007-1.095-0.831-1.873-2.415-3.456-3.189-4.2211.2690.7192.4853.2092.6093.6853.0851.8651.0171.290-0.0663.2833.1363.5353.7974.9542.6842.765

44.8543.9144.1144.5445.7943.5444.9943.2243.0242.6444.2044.0642.3943.4345.8644.8644.4443.5144.2544.4347.6648.7148.6246.7447.1647.6849.0644.9744.0744.8046.5247.8649.2249.5351.6752.6853.2052.2246.2848.6145.8644.8245.1046.1447.35

LLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLL

ONCCCCCCONCCCCCCONCCCCCCCCOCONCCCCNCNNCONCCCO

NCACBOGCONCACBCGOD1ND2CONCACBCGCD1CD2CONCACBCGCDOE1OE2CONCACBOGCONCACONCACBCG2

SER LSER LSER LSER LSER LSER LASN LASN LASN LASN LASN LASN LASN LASN LLEU LLEU LLEU LLEU LLEU LLEU LLEU LLEU LGLU LGLU LGLU LGLU LGLU LGLU LGLU LGLU LGLU LSER LSER LSER LSER LSER LSER LGLY LGLY LGLY LGLY LILE LILE LILE LILE L

525252525252535353535353535354545454545454545555555555555555555656565656565757575758585858

58.14659.17860.48260.24958.71859.46757.40356.75055.79256.54757.18056.49955.99854.93256.62656.04457.08056.67656.43457.73854.74954.70153.62652.36851.29449.97149.16949.76947.88552.36052.87051.75051.75550.93350.92651.16350.18651.87451.42452.20452.15752.89553.50853.53454.205

43.43843.62442.89441.53943.18643.29742.79042.27241.11539.81739.53839.01843.32543.81843.65144.64844.97846.17347.43746.54044.15143.10744.85944.47845.40445.20543.96943.07843.88444.66245.53243.78143.83742.61042.84645.19045.76145.79647.04948.19349.23148.02649.17748.87549.855

1.6500.5830.9551.329-0.849-1.810-0.932-2.150-1.787-1.926-2.944-0.851-2.976-2.633-4.141-5.060-6.148-7.022-6.202-8.068-5.720-6.358-5.601-6.116-5.592-6.300-5.835-5.176-6.132-7.650-8.219-8.303-9.703-10.158-11.533-10.225-9.731-11.127-11.688-11.119-11.753-9.960-9.257-7.833-7.156

44.6445.9642.7543.6247.1948.3849.2051.2652.8055.5859.6955.7951.9053.1652.0153.3854.1554.4655.0956.2453.7254.4553.5155.1155.2155.6457.1957.6056.5755.9055.8156.8058.4258.4062.5457.3057.5657.3756.9656.7958.7955.4153.9651.4350.04

LLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLL

NCCOCONCCCONCONCCCCCCONCCCCOOCONCCOCONCCONCCC

CG1CD1CONCDCACBCGCONCACBCONCACBCGCDNECZNH1NH2CONCACBCGCD1CD2CE1CE2CZCONCACBOGCON

ILE LILE LILE LILE LPRO LPRO LPRO LPRO LPRO LPRO LPRO LALA LALA LALA LALA LALA LARG LARG LARG LARG LARG LARG LARG LARG LARG LARG LARG LPHE LPHE LPHE LPHE LPHE LPHE LPHE LPHE LPHE LPHE LPHE LSER LSER LSER LSER LSER LSER LGLY L

585858585959595959595960606060606161616161616161616161626262626262626262626263636363636364

52.12151.21254.87855.49355.39954.70656.80056.94355.58657.86757.70958.97060.16561.26660.85461.78960.50360.97960.49160.28459.85058.42257.73358.34456.47560.56561.10959.52959.03257.46756.73756.52256.36555.87355.85955.52859.62759.36960.11560.62762.22162.86760.38760.26060.505

48.76950.08249.29448.28350.47351.75250.60352.05852.66450.26950.42349.76749.33048.62350.49450.22551.75252.80354.16354.23955.65455.95556.56956.91656.90552.56153.12051.81151.63251.46952.75453.65153.12254.85354.35055.21050.30549.28150.24449.03148.90250.20449.14650.20448.022

-7.308-7.601-9.751-9.888-10.051-10.212-10.428-10.742-10.254-9.460-8.128-10.063-9.309-10.235-8.512-7.714-8.815-7.943-8.394-9.802-10.234-10.333-9.387-8.329-9.543-6.456-5.595-6.212-4.935-4.961-5.178-4.150-6.376-4.358-6.619-5.657-4.485-5.181-3.287-2.616-2.650-2.559-1.139-0.588-0.459

51.2550.7254.1555.2153.5352.3253.6051.9551.2854.4755.9654.3154.0253.4153.8853.5653.4652.9754.3955.5758.7560.4361.4261.4960.7851.5051.5750.0049.9347.9348.9248.2048.6748.8249.2147.0750.0551.1248.7949.3348.4452.9649.5250.1449.55

LLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLL

CCCONCCCCCONCCCONCCCCNCNNCONCCCCCCCCCONCCOCON

CACONCACBOGCONCACONCACBOGCONCACBCGCDNECZNH1NH2CONCACBOG1CG2CONCACBCGOD1OD2CO

GLY LGLY LGLY LSER LSER LSER LSER LSER LSER LGLY LGLY LGLY LGLY LSER LSER LSER LSER LSER LSER LARG LARG LARG LARG LARG LARG LARG LARG LARG LARG LARG LTHR LTHR LTHR LTHR LTHR LTHR LTHR LASP LASP LASP LASP LASP LASP LASP LASP L

646464656565656565666666666767676767676868686868686868686868696969696969697070707070707070

60.23661.15961.70861.36562.18663.66963.90361.94261.16362.64062.94462.09761.40162.23661.46962.28963.44061.11261.56660.22659.75260.94360.57961.29062.25062.79662.47763.64059.05458.09259.56858.93559.12860.47458.18559.54959.27060.44461.09562.56562.64862.03263.30460.96361.438

47.98146.98046.06347.19246.23746.48647.88046.32547.10545.35545.16744.04443.29443.93742.90141.61041.77743.30144.29942.49242.79942.83042.31140.98840.75739.53738.58439.28744.15144.43844.98046.25646.54146.22645.66647.39848.57347.03148.08348.16348.80749.86048.25447.85746.878

0.9661.6571.0502.9673.7073.3933.1975.2405.7225.8967.2857.8957.2259.2199.8989.89910.72811.33011.86911.93813.28414.24315.63515.90214.81914.70615.56313.70213.35412.65914.27514.55516.04416.40516.87213.73413.94912.79312.01812.43313.81713.99214.69410.5119.956

49.9250.3151.4950.1251.6551.7954.6552.2351.5053.8354.6555.4056.1756.7457.0056.1252.4258.8058.1460.1462.8566.3671.2075.5379.2781.8481.9282.1162.5363.4761.1558.9960.1962.6959.5756.9658.3254.0952.2055.6058.3959.5561.4550.3250.21

LLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLL

CCONCCOCONCCONCCOCONCCCCNCNNCONCCOCCONCCCOOCO

NCACBCGCD1CD2CE1CE2CZCONCACBOG1CG2CONCACBCGCD1CD2CONCACBOG1CG2CONCACBCG2CG1CD1CONCACBCG

PHE LPHE LPHE LPHE LPHE LPHE LPHE LPHE LPHE LPHE LPHE LTHR LTHR LTHR LTHR LTHR LTHR LTHR LLEU LLEU LLEU LLEU LLEU LLEU LLEU LLEU LTHR LTHR LTHR LTHR LTHR LTHR LTHR LILE LILE LILE LILE LILE LILE LILE LILE LASN LASN LASN LASN L

717171717171717171717172727272727272737373737373737374747474747474757575757575757576767676

60.23660.06258.63358.37557.80358.72857.59458.51557.95560.33160.17260.79960.89962.36963.00363.10760.31160.36859.86559.33857.99857.44857.16556.16460.24460.48960.74561.67863.01463.44864.00461.19260.57561.23960.82459.71659.07558.59757.61562.05762.64762.55163.75464.91066.156

48.80348.76248.31346.95846.86145.81845.61344.56744.46150.12551.18350.06051.27951.70951.00951.39051.07950.00452.16952.20252.82853.06251.76953.76653.23954.29652.91053.80753.05452.84653.73854.06953.15655.34555.80156.81357.02956.28057.25356.41457.34355.69756.08855.46756.228

9.8558.3918.0648.6529.9137.95210.4808.5269.7947.7338.3286.4695.6685.5714.5006.8744.2663.6843.6222.2962.2680.8790.2370.8481.5732.1450.402-0.355-0.4580.943-1.237-1.791-2.361-2.184-3.394-3.255-4.756-2.371-2.112-4.104-3.656-5.093-5.754-5.119-5.432

47.2245.4443.2343.3441.6242.4940.3441.4941.1345.2146.5844.2045.0346.3252.2045.3143.7343.7641.7740.4740.2440.6740.5039.5741.3940.3341.4144.6545.2947.0241.8746.1148.0746.9349.3749.6648.2949.0849.4451.1849.9554.3656.0656.7858.44

LLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLL

NCCCCCCCCCONCCOCCONCCCCCCONCCOCCONCCCCCCONCCC

OD1ND2CONCDCACBCGCONCACBCG1CG2CONCACBCGCDOE1OE2CONCACBCONCACBCGOD1OD2CONCACBCGOD1

ASN LASN LASN LASN LPRO LPRO LPRO LPRO LPRO LPRO LPRO LVAL LVAL LVAL LVAL LVAL LVAL LVAL LGLU LGLU LGLU LGLU LGLU LGLU LGLU LGLU LGLU LALA LALA LALA LALA LALA LASP LASP LASP LASP LASP LASP LASP LASP LASP LASP LASP LASP LASP L

767676767777777777777778787878787878797979797979797979808080808081818181818181818282828282

66.08367.26263.85463.96463.82764.02263.65464.19163.67962.20261.24962.09060.82660.87859.64960.81460.38461.12559.11558.56858.06459.10158.60659.54757.39057.31356.70856.86555.87755.73654.49953.86354.10652.99152.63551.24550.18151.14653.02552.03054.07554.14455.58856.24055.485

57.36755.61755.73954.55256.68956.42558.11858.74357.74158.62758.10259.73360.40461.34162.19160.50661.04661.66661.02761.85760.85659.87258.94658.24359.00962.58362.21363.43564.40565.16763.90064.48962.82462.07961.15060.56561.32259.34361.23860.67561.30860.59760.27659.34258.500

-5.916-5.265-7.120-7.421-7.994-9.423-7.725-9.015-10.056-7.678-8.307-6.904-6.770-5.622-5.632-4.300-8.097-8.805-8.313-9.363-10.490-10.986-12.112-12.667-12.468-8.913-7.941-9.740-9.435-10.630-9.041-8.186-9.738-9.383-10.581-10.455-10.285-10.407-8.054-7.720-7.279-6.012-5.666-6.753-7.287

61.3557.1056.0357.7155.4854.9555.3554.2154.1755.6155.4055.6655.0655.0854.5253.1954.9055.1353.4553.7655.6159.2561.3862.4061.9352.6652.3152.0752.1852.0951.7649.5251.0752.0054.5457.3258.7059.7550.6349.7348.8348.8949.8852.1452.41

LLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLL

ONCONCCCCCONCCCCCONCCCCOOCONCCCONCCCOOCONCCCO

OD2CONCACBCG1CG2CONCACBCONCACBOG1CG2CONCACBCGCD1CE1CD2CE2CZOHCONCACBCGCD1CE1CD2CE2CZOHC

ASP LASP LASP LVAL LVAL LVAL LVAL LVAL LVAL LVAL LALA LALA LALA LALA LALA LTHR LTHR LTHR LTHR LTHR LTHR LTHR LTYR LTYR LTYR LTYR LTYR LTYR LTYR LTYR LTYR LTYR LTYR LTYR LTYR LTYR LTYR LTYR LTYR LTYR LTYR LTYR LTYR LTYR LTYR L

828282838383838383838484848484858585858585858686868686868686868686868787878787878787878787

57.44253.67353.81953.07952.63852.16553.18051.05051.40850.45951.46650.50350.56350.77451.89449.86350.12348.92448.90949.09950.38949.68851.33551.66953.12353.48153.69653.91353.33053.52553.79453.88851.39851.81950.67950.45448.94648.19547.70846.92947.71047.05746.62645.85150.917

59.34361.39660.94762.56063.35764.84865.48664.87762.65462.41962.37761.59260.21161.44161.70060.72760.30260.59761.98460.16958.81258.20158.22856.82756.64457.13158.45658.82856.28956.76958.03358.48056.22156.82655.06454.39254.32355.57356.11057.27756.08657.27357.82958.91652.985

-6.965-4.814-3.655-5.096-4.005-4.323-5.076-5.086-3.519-4.303-2.239-1.600-2.223-0.1010.3290.5651.9822.8592.9534.2201.9251.2322.6922.6662.2430.8490.561-0.781-0.211-1.598-1.809-3.2513.9345.0173.9455.2495.5305.4994.3224.4006.6966.7435.4305.4405.331

54.5648.6548.0447.1246.7647.5448.0048.8745.3245.5543.6342.8043.1141.6142.1139.6041.0741.8843.5042.7341.8642.1441.1742.1540.6740.3337.5638.3538.7637.3140.0237.6744.1446.2942.5142.4041.0639.2537.9037.8639.4537.4137.6240.7243.25

LLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLL

OCONCCCCCONCCCONCCOCCONCCCCCCCCOCONCCCCCCCCOC

ONCACOCBSGNCACBCGCDOE1NE2CONCACBCGCDOE1NE2CONCACBOGCONCACBCGOD1ND2CONCACBCGCDOE1

TYR LCYS LCYS LCYS LCYS LCYS LCYS LGLN LGLN LGLN LGLN LGLN LGLN LGLN LGLN LGLN LGLN LGLN LGLN LGLN LGLN LGLN LGLN LGLN LGLN LSER LSER LSER LSER LSER LSER LASN LASN LASN LASN LASN LASN LASN LASN LGLU LGLU LGLU LGLU LGLU LGLU L

878888888888888989898989898989899090909090909090909191919191919292929292929292939393939393

50.96251.32451.63250.50549.62252.98652.92850.46049.29248.12546.97146.82546.83946.88849.75650.44649.47549.73750.49149.62548.65448.92147.54648.50547.33148.79347.84147.99147.14848.26047.81849.09649.55350.95551.43951.34552.08948.65048.54747.86746.91747.66446.78147.57047.033

52.29852.58551.24950.61751.29551.03952.04249.28248.54048.52347.79346.37046.25845.30747.13646.58046.67245.30745.29645.80144.71043.58345.10544.35244.70643.07242.00741.51642.51540.85239.74141.13640.10640.29339.10238.02239.33739.77438.67740.69440.51140.79441.35241.63142.328

4.2736.5576.8337.5978.1297.6549.1857.5288.1057.1407.7046.9565.7307.7938.4247.5989.63310.05111.39812.58513.15513.01813.75610.09010.3969.7639.6058.0527.44810.53510.35911.52612.40412.86713.65913.19914.77313.45213.78713.78414.84716.12717.22518.61319.596

42.8744.1344.8844.5543.3844.7545.5744.1844.1042.7142.2742.9541.3738.4445.0644.9544.1744.7942.3444.5246.5146.9346.4745.8044.6647.0450.2450.8851.6251.0351.4351.6952.6853.6454.6655.4653.6652.8451.4854.2156.3358.2764.9169.2769.83

LLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLL

ONCCOCSNCCCCONCONCCCCONCONCCOCONCCCONCONCCCCO

OE2CONCACBCGOD1OD2CONCDCACBCGCONCACBCGCD2CE2CE3CD1NE1CZ2CZ3CH2CONCACBOG1CG2CONCACBCGCD1CD2

GLU LGLU LGLU LASP LASP LASP LASP LASP LASP LASP LASP LPRO LPRO LPRO LPRO LPRO LPRO LPRO LTRP LTRP LTRP LTRP LTRP LTRP LTRP LTRP LTRP LTRP LTRP LTRP LTRP LTRP LTHR LTHR LTHR LTHR LTHR LTHR LTHR LPHE LPHE LPHE LPHE LPHE LPHE L

939393949494949494949495959595959595969696969696969696969696969697979797979797989898989898

48.75345.69345.83044.53243.34642.14242.07642.69641.46343.19043.64842.67242.46142.31241.37642.06343.39644.30043.35444.28944.00344.18144.08444.23143.83144.36944.44644.32743.87544.03044.30443.28245.48045.61046.17947.33745.19046.56147.46546.37147.15846.25745.49244.26045.845

41.16441.40342.48740.97541.75040.80939.99740.31039.00842.58942.18043.77744.71444.34845.51046.11744.75945.38944.39245.07444.78043.37242.81541.36143.33142.32741.11940.52142.46741.02246.63947.21247.27948.69249.03248.27048.60249.33148.65350.62051.35552.15751.27550.69051.317

18.67914.79214.51215.32915.36415.29413.82612.81413.64816.55517.66316.38717.48915.08715.43616.79114.18814.64312.86711.94710.47810.0978.8278.9767.57710.94110.3067.9396.4676.64012.16512.33412.17212.32513.64513.80614.78411.31510.85211.20410.2439.3018.2338.5496.909

71.1655.4655.1354.5353.2354.7057.4357.1461.0451.9954.0548.8347.9948.0949.0947.7146.8747.7345.9745.5245.6845.8646.6446.9847.5844.8945.5946.2848.8447.1743.7042.6642.3542.6341.0642.4342.1542.1140.7242.7944.7244.1945.9444.3843.71

LLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLL

OCONCCCOOCONCCCCCONCCCCCCCNCCCCONCCOCCONCCCCC

CE1CE2CZCONCACONCACONCACONCACBOG1CG2CONCACBCGCDCENZCONCACBCGCD1CD2CONCACBCG

PHE LPHE LPHE LPHE LPHE LGLY LGLY LGLY LGLY LGLY LGLY LGLY LGLY LGLY LGLY LGLY LGLY LTHR LTHR LTHR LTHR LTHR LTHR LTHR LLYS LLYS LLYS LLYS LLYS LLYS LLYS LLYS LLYS LLEU LLEU LLEU LLEU LLEU LLEU LLEU LLEU LGLU LGLU LGLU LGLU L

989898989899999999100100100100101101101101102102102102102102102103103103103103103103103103104104104104104104104104105105105105

43.57945.14243.99048.02147.53949.15549.80949.05148.14349.53149.02449.19948.79050.01350.42651.66351.93452.29153.41154.62655.23655.66553.15452.86753.05852.81652.19151.60950.96750.58749.21854.08955.07054.13655.23755.45056.50457.73656.68054.88654.01355.75055.75955.53954.018

49.89150.54449.84452.42453.02052.85854.07555.33755.39256.44157.75258.37359.44357.75758.40659.27959.90459.44260.31359.53459.08660.32960.97660.24062.32063.20164.44565.47764.74965.50164.66163.52863.98763.20363.49362.27962.48762.66561.29364.66964.59565.62166.68167.92167.996

7.6305.9526.32311.03211.93210.46710.92110.5659.50911.24711.0589.6579.3138.8447.6507.6208.5876.4336.2555.9657.1155.1724.8303.8414.8093.6734.2123.2211.9110.5270.1582.9373.5291.6400.821-0.094-1.172-0.408-2.010-0.160-0.991-0.180-1.104-0.352-0.086

44.1444.4043.7745.3946.1745.8145.0646.3145.4245.8845.3045.4345.5745.6245.8546.1944.6145.3645.2844.8344.0344.0146.6645.3547.1848.5050.9056.5760.5160.7564.5149.1246.8949.8850.1750.1051.6150.9151.2850.5150.3652.4954.1155.1061.17

LLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLL

CCCCONCCONCCONCCONCCOCCONCCCCCNCONCCCCCCONCCC

CDOE1OE2CONCACBCG2CG1CD1CONCACBCGCDCENZCONCACBCGCDNECZNH1NH2CONCACBCONCACBCGOD1OD2C

GLU LGLU LGLU LGLU LGLU LILE LILE LILE LILE LILE LILE LILE LILE LLYS LLYS LLYS LLYS LLYS LLYS LLYS LLYS LLYS LARG LARG LARG LARG LARG LARG LARG LARG LARG LARG LARG LALA LALA LALA LALA LALA LASP LASP LASP LASP LASP LASP LASP L

105105105105105106106106106106106106106107107107107107107107107107108108108108108108108108108108108109109109109109110110110110110110110

53.63754.42552.65256.95458.11656.64457.74557.34958.59256.77757.70258.34857.60459.71460.47861.78761.72663.14563.00264.25560.78561.07960.48960.60259.37058.12257.19457.72857.27756.28657.81761.10961.24761.41861.79962.04060.61559.41060.92059.89260.51161.12860.92861.87059.125

68.79068.42069.66166.70866.33367.28567.67067.40667.70365.99965.01669.01969.92869.12470.43070.55270.32570.59471.21271.13070.78069.88872.05272.58672.33672.92673.34774.54475.00274.38476.09373.98174.52674.55376.01576.29676.95076.62878.05378.96680.15779.79778.73080.62179.430

1.2072.1791.163-2.082-1.762-3.223-4.139-5.589-6.534-5.661-5.232-3.972-3.826-3.982-4.003-3.283-1.955-1.3640.0710.893-5.419-6.256-5.691-6.940-7.752-7.302-8.373-9.051-10.208-10.896-10.739-6.858-5.783-8.058-8.199-9.655-7.667-7.921-6.998-6.545-5.837-4.443-3.852-3.807-7.775

64.6367.6465.1654.0053.0054.7556.7056.2856.7357.3756.7157.2157.9357.7358.7358.9261.5063.5665.2767.1758.5459.8357.7156.7956.2557.1158.2259.5860.7360.1860.3857.2057.3756.6256.0953.7956.4356.1656.1856.8656.8158.5459.5259.9257.69

LLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLL

COOCONCCCCCCONCCCCCNCONCCCCNCNNCONCCCONCCCOOC

ONCACBCONCACBCONCDCACBCGCONCACBOG1CG2CONCACBCG1CG2CONCACBOGCONCACBCG2CG1CD1C

ASP LALA LALA LALA LALA LALA LALA LALA LALA LALA LALA LPRO LPRO LPRO LPRO LPRO LPRO LPRO LTHR LTHR LTHR LTHR LTHR LTHR LTHR LVAL LVAL LVAL LVAL LVAL LVAL LVAL LSER LSER LSER LSER LSER LSER LILE LILE LILE LILE LILE LILE LILE L

110111111111111111112112112112112113113113113113113113114114114114114114114115115115115115115115116116116116116116117117117117117117117

59.67257.83856.86956.07055.94155.37655.80754.85055.22253.37052.98852.47452.64351.07450.38451.27150.51650.92249.39248.63148.30049.51747.35247.31546.52947.09346.02646.52645.49847.73344.89645.06743.69742.53641.99343.12741.51741.39640.80739.70540.03439.91139.17639.50938.324

79.41779.72380.17179.03481.17980.89282.36883.31084.80682.89382.40683.23484.04383.01583.51384.52983.92085.03183.53084.21883.28982.94284.01084.52983.54885.83186.29687.33987.84786.74886.83287.61286.49387.04086.00485.80987.42186.70988.52988.94990.31891.54590.56191.72888.847

-8.905-7.595-8.619-9.159-7.991-6.956-8.618-8.173-8.826-8.402-9.455-7.505-6.244-7.777-6.451-5.848-8.805-8.877-9.334-10.276-11.360-11.940-12.458-9.570-9.242-9.299-8.435-7.568-6.585-6.861-9.187-10.165-8.747-9.514-10.433-11.254-8.528-7.486-8.785-7.955-7.214-8.193-5.851-5.135-8.605

59.3556.1155.1952.1055.8055.3756.0556.0755.3156.0756.8955.8054.6854.6954.6853.6554.7455.3954.3854.7255.0856.7154.0255.9355.9555.1155.6555.2954.3755.5156.7757.4957.4459.9659.4463.3761.3062.3862.2963.5964.2463.9363.8263.1764.65

LLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLL

ONCCCONCCCONCCCCCONCCOCCONCCCCCONCCOCONCCCCCC

ONCACBCGCD1CD2CE1CE2CZCONCDCACBCGCONCDCACBCGCONCACBOGCONCACBOGCONCACBCGCDOE1OE2

ILE LPHE LPHE LPHE LPHE LPHE LPHE LPHE LPHE LPHE LPHE LPHE LPRO LPRO LPRO LPRO LPRO LPRO LPRO LPRO LPRO LPRO LPRO LPRO LPRO LPRO LSER LSER LSER LSER LSER LSER LSER LSER LSER LSER LSER LSER LGLU LGLU LGLU LGLU LGLU LGLU LGLU L

117118118118118118118118118118118118119119119119119119119120120120120120120120121121121121121121122122122122122122123123123123123123123

38.13537.30136.01135.65036.65037.74036.44838.64037.33338.37834.95234.82134.15134.18333.09432.68933.93431.94131.81931.01830.91929.87129.14930.18528.91728.74328.31127.43227.09426.58626.13225.75325.40624.02723.32624.06123.12822.36723.24522.35222.64221.47621.98021.54322.830

88.84288.66788.51487.07086.30785.73586.08785.06285.35684.84689.19288.89990.10390.60390.77191.92992.08789.87888.99190.15891.39889.23789.86690.86889.15490.11388.00887.86586.41285.86088.60288.75989.00589.56689.89289.39588.62089.03287.35186.39185.08684.05782.62081.64982.491

-9.868-7.783-8.316-8.575-9.398-8.812-10.734-9.583-11.483-10.967-7.470-6.264-8.061-9.460-7.290-8.220-9.087-7.085-7.820-6.195-5.392-5.969-4.837-4.253-7.152-7.840-7.406-8.562-8.743-7.505-8.241-7.076-9.291-9.093-10.400-11.455-8.362-7.482-8.720-8.170-8.917-9.091-9.416-8.701-10.349

66.1065.7067.4868.0068.5769.9167.9369.9468.4368.5668.6469.4969.2268.8769.1668.7169.4069.4869.6670.2770.1571.1470.7670.8171.9072.2873.4975.0975.1275.7476.4176.2277.9279.3279.4681.3979.7179.6179.8480.6282.3284.7686.6388.1787.03

LLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLL

ONCCCCCCCCCONCCCCCONCCCCCONCCOCONCCOCONCCCCOO

CONCACBCGCDOE1NE2CONCACBCGCD1CD2CONCACBOG1CG2CONCACBOGCONCACONCACONCACBCO

GLU LGLU LGLN LGLN LGLN LGLN LGLN LGLN LGLN LGLN LGLN LLEU LLEU LLEU LLEU LLEU LLEU LLEU LLEU LTHR LTHR LTHR LTHR LTHR LTHR LTHR LSER LSER LSER LSER LSER LSER LGLY LGLY LGLY LGLY LGLY LGLY LGLY LGLY LALA LALA LALA LALA LALA L

123123124124124124124124124124124125125125125125125125125126126126126126126126127127127127127127128128128128129129129129130130130130130

22.34121.29323.48623.62825.11925.59027.16627.73427.81123.22222.71423.53123.19223.62324.77025.49725.71221.67821.22220.89319.47618.74019.10619.11219.18818.21819.97219.76920.70020.07519.95919.47720.66121.10722.57822.94323.39824.79525.75025.39126.97727.99628.26929.24829.693

86.30886.13686.50686.41286.10386.08586.20886.13886.38587.74787.84188.79790.18591.16292.12291.65992.31990.29290.37290.20790.11689.57788.20990.31389.14889.26288.12887.30786.06084.89387.97487.36789.13089.68989.51789.96088.77488.51989.16189.35089.49589.86091.28288.97589.059

-6.609-5.979-5.988-4.536-4.212-2.803-2.726-1.666-3.834-3.926-2.784-4.708-4.268-5.306-5.094-3.878-6.364-4.087-2.956-5.150-4.932-6.127-6.272-7.442-3.809-3.161-3.608-2.421-2.431-1.916-1.042-0.088-0.9150.3840.9132.0020.1710.509-0.515-1.659-0.095-1.089-0.981-0.7260.402

79.8579.9479.1778.8477.4775.5275.3775.0674.9579.3878.5780.1480.8279.7478.7678.2578.1181.7182.1581.9482.4382.8784.0183.7182.0383.1681.2980.3081.2682.1778.9279.1577.2776.6676.0075.5675.1673.7972.5971.6671.1269.7869.1669.1469.40

LLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLL

CONCCCCONCONCCCCCCONCCOCCONCCOCONCCONCCONCCCO

NCACBOGCONCACBCG1CG2CONCACBCG1CG2CONCACOCBSGNCACBCGCD1CD2CE1CE2CZCONCACBCGCD1CD2CO

SER LSER LSER LSER LSER LSER LVAL LVAL LVAL LVAL LVAL LVAL LVAL LVAL LVAL LVAL LVAL LVAL LVAL LVAL LCYS LCYS LCYS LCYS LCYS LCYS LPHE LPHE LPHE LPHE LPHE LPHE LPHE LPHE LPHE LPHE LPHE LLEU LLEU LLEU LLEU LLEU LLEU LLEU LLEU L

131131131131131131132132132132132132132133133133133133133133134134134134134134135135135135135135135135135135135136136136136136136136136

29.68530.95430.76129.91131.97731.64033.14134.23634.81935.78633.79735.28735.68935.67436.50835.84536.66634.49037.77937.83838.80840.17040.91041.02240.96342.52541.46542.32041.91640.56340.19939.57038.91838.27437.97943.69544.06544.47545.90246.46646.19744.80947.20646.46146.648

88.05387.32485.77985.26987.77487.84788.17788.63289.97290.54690.97987.54587.05387.09285.92284.81283.56084.53686.29687.02685.73885.86684.50783.71686.78387.37384.20283.02482.23181.66780.89481.92780.41481.40580.72383.39084.43082.61582.63682.92684.38084.34884.58881.27080.361

-1.568-1.317-1.366-0.267-2.347-3.602-1.850-2.718-2.286-3.235-2.012-2.681-1.599-3.864-4.004-4.879-4.734-4.496-4.687-5.766-4.151-4.711-4.875-3.947-3.760-4.465-6.034-6.337-7.608-7.504-6.353-8.426-6.220-8.208-7.131-6.360-6.793-5.732-5.797-4.349-3.849-3.487-2.663-6.220-5.363

67.8366.3866.4565.9565.4665.3364.0063.1363.1862.1063.4662.5261.7162.2861.1360.7961.2160.8760.8459.3960.5560.8058.8358.5462.4966.6958.1058.0057.9959.9860.2660.5260.7960.2460.1757.3759.0856.2056.0155.0053.4852.5753.6855.4655.72

LLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLL

NCCOCONCCCCCONCCCCCONCCOCSNCCCCCCCCCONCCCCCCO

NCACBCGOD1ND2CONCACBCGOD1ND2CONCACBCGCD1CD2CE1CE2CZCONCACBCGCD1CE1CD2CE2CZOHCONCDCACBCGC

ASN LASN LASN LASN LASN LASN LASN LASN LASN LASN LASN LASN LASN LASN LASN LASN LPHE LPHE LPHE LPHE LPHE LPHE LPHE LPHE LPHE LPHE LPHE LTYR LTYR LTYR LTYR LTYR LTYR LTYR LTYR LTYR LTYR LTYR LTYR LPRO LPRO LPRO LPRO LPRO LPRO L

137137137137137137137137138138138138138138138138139139139139139139139139139139139140140140140140140140140140140140140141141141141141141

46.69646.90845.91244.57643.61144.48648.28049.02348.71750.01949.94848.84547.73849.16451.28252.08551.49352.68652.24351.35151.88950.02051.03349.15349.68553.47952.96754.74355.49156.22257.03258.31059.07056.48957.18958.48259.12256.51557.13256.91458.09756.38157.43658.11255.060

81.12579.85379.84879.53279.41879.39679.48880.36378.23477.76177.67076.76177.16875.45178.40978.95878.36978.99180.10579.67979.23179.85478.83279.65579.14578.03576.99278.30777.53276.38475.42975.77674.86074.23173.39873.73172.90378.43679.31878.18978.90677.11477.04278.41777.398

-7.504-8.217-9.315-8.824-9.556-7.490-8.641-9.044-8.388-8.934-10.515-10.939-11.022-11.148-8.462-9.222-7.146-6.586-5.715-4.491-3.410-4.515-2.264-3.432-2.293-5.987-5.659-5.712-4.737-5.565-4.718-4.260-3.430-4.313-3.442-3.033-2.208-4.108-4.849-2.837-2.277-1.909-0.809-0.784-1.338

54.7154.0253.1354.0754.8753.3653.4252.7353.5652.8253.0753.9054.0556.1552.7352.9951.9150.6050.7448.2546.2247.5744.3846.9946.1050.7451.4250.6951.0250.2150.5150.9051.7350.2949.9750.7151.2852.4053.0253.2453.9453.8254.1754.6555.01

LLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLL

NCCCONCONCCCONCONCCCCCCCCCONCCCCCCCCOCONCCCCC

ONCACBCGCDCENZCONCACBCGOD1OD2CONCACBCG2CG1CD1CONCACBCGOD1ND2CONCACBCG1CG2CONCACBC

PRO LLYS LLYS LLYS LLYS LLYS LLYS LLYS LLYS LLYS LASP LASP LASP LASP LASP LASP LASP LASP LILE LILE LILE LILE LILE LILE LILE LILE LASN LASN LASN LASN LASN LASN LASN LASN LVAL LVAL LVAL LVAL LVAL LVAL LVAL LALA LALA LALA LALA L

141142142142142142142142142142143143143143143143143143144144144144144144144144145145145145145145145145146146146146146146146147147147147

54.45054.52253.10352.81153.68753.10053.39252.24752.74251.58953.69553.50954.78755.36954.60356.38153.14453.78151.99251.46050.84849.49550.45950.21850.51750.02550.39849.47450.18050.71150.06451.80348.75049.35147.43846.55545.30344.30744.67445.90045.59845.67145.06446.13744.014

78.37076.46076.61675.33575.26674.38172.90072.06977.84678.21978.30179.45279.66278.20877.55177.58980.70781.10081.22782.46082.19881.52783.39682.95283.18382.63384.45985.21685.97384.96084.62984.32486.16386.78286.22687.23486.51786.21187.50888.25287.92089.43690.60191.68691.255

-1.550-0.588-0.0290.8002.0593.2132.8883.0310.9101.0531.6472.5443.4353.8814.6783.3501.7770.8322.1391.5790.2400.333-0.447-1.9992.5163.4472.3523.1734.3845.4386.5625.0352.3151.5732.4781.9241.0791.8720.1602.9104.0762.4203.1763.5852.324

54.0556.7858.3159.2062.4466.3968.8071.0457.7756.4758.6460.5963.7268.1171.2368.5259.8659.9159.2057.8457.6957.2956.9758.7457.8457.8258.3258.9061.3365.5367.5067.7858.3357.4157.8658.0657.9557.7858.4657.6458.2157.3357.7155.8757.31

LLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLL

ONCCCCCNCONCCCOOCONCCCCCCONCCCONCONCCCCCONCCC

ONCACBCGCD2CE2CE3CD1NE1CZ2CZ3CH2CONCACBCGCDCENZCONCACBCG2CG1CD1CONCACBCGOD1OD2CONCACON

ALA LTRP LTRP LTRP LTRP LTRP LTRP LTRP LTRP LTRP LTRP LTRP LTRP LTRP LTRP LLYS LLYS LLYS LLYS LLYS LLYS LLYS LLYS LLYS LILE LILE LILE LILE LILE LILE LILE LILE LASP LASP LASP LASP LASP LASP LASP LASP LGLY LGLY LGLY LGLY LSER L

147148148148148148148148148148148148148148148149149149149149149149149149150150150150150150150150151151151151151151151151152152152152153

44.22342.85141.82140.46240.28839.69439.62239.24140.54240.15739.10538.71938.65241.85942.07341.70541.49042.70544.01745.19146.31047.55440.23640.08339.29738.11836.89335.67237.11535.80138.19037.92038.61438.69837.33036.51536.90335.49039.77139.50141.00542.13542.40043.49741.354

91.49991.45392.21891.58490.29190.08588.68590.94589.00588.01088.18790.44989.05293.66993.97294.57695.97096.77096.27597.19997.13297.63196.51396.48096.97597.64997.08297.14895.61794.84699.15599.65199.893101.335101.823102.376102.148103.004101.714102.350101.233101.650100.699100.184100.501

1.1012.8942.2362.5651.8530.5410.329-0.4542.3711.528-0.854-1.634-1.8352.7053.8761.7272.0711.6012.2161.8832.9282.3461.3930.1792.2381.7092.4201.4832.8072.9001.9613.0480.9191.0801.5630.400-0.7440.6602.1163.1291.8582.6843.8584.0434.688

58.0457.8758.8957.3357.6657.5557.1556.5658.0357.4856.9457.2257.6659.6858.3860.9262.7062.7365.7967.3068.0669.7564.5565.4366.2968.2467.6166.7468.8768.9469.9370.6872.1575.1176.6078.0080.1278.8276.2777.7676.1877.9979.5880.5679.95

LLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLL

ONCCCCCCCNCCCCONCCCCCNCONCCCCCCONCCCOOCONCCON

CACBOGCONCACBCGCDOE1OE2CONCACBCGCDNECZNH1NH2CONCACBCGCDOE1NE2CONCACBCGOD1ND2CONCAC

SER LSER LSER LSER LSER LGLU LGLU LGLU LGLU LGLU LGLU LGLU LGLU LGLU LARG LARG LARG LARG LARG LARG LARG LARG LARG LARG LARG LGLN LGLN LGLN LGLN LGLN LGLN LGLN LGLN LGLN LASN LASN LASN LASN LASN LASN LASN LASN LGLY LGLY LGLY L

153153153153153154154154154154154154154154155155155155155155155155155155155156156156156156156156156156157157157157157157157157158158158

41.52840.48839.49341.39740.62542.23842.19943.43143.69344.93445.68845.15540.92440.45540.48039.51538.39737.15136.20034.87733.64633.46432.56440.14041.03539.66639.81140.77042.23243.07842.76544.16938.45938.33437.43536.10935.30033.88233.57333.03235.38034.96735.10334.18335.024

99.673100.083100.91598.18697.77497.41595.95695.49093.98693.66294.57392.48695.41095.94294.33893.44193.26493.96593.33794.02593.43792.12694.20992.07591.59691.49090.08390.09990.22890.93192.02690.28289.28888.06190.01589.48790.70090.32389.13291.33988.98289.81087.64287.16386.671

5.8786.9316.3365.5544.6976.2716.2177.0006.9097.7108.0117.9896.8897.8846.2206.7615.7856.1907.2387.1537.1467.2746.9987.0776.3228.1968.6559.8309.42110.42710.84610.8578.9528.7339.3419.54710.07510.59210.65210.9548.2987.4088.2227.1736.129

80.2479.8680.5680.2879.9280.8182.0182.5883.8885.0086.2485.1782.3081.9782.6583.0383.3784.9286.7788.2588.4287.3689.7682.9983.9781.9980.7680.7280.8082.0582.8082.6680.1880.1878.7177.0378.9780.5682.3281.0574.7875.0671.8067.2665.35

LLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLL

CCOCONCCCCOOCONCCCCNCNNCONCCCCONCONCCCONCONCC

ONCACBCG1CG2CONCACBCGCD1CD2CONCACBCGOD1ND2CONCACBOGCONCACBCGCD2CE2CE3CD1NE1CZ2CZ3CH2CON

GLY LVAL LVAL LVAL LVAL LVAL LVAL LVAL LLEU LLEU LLEU LLEU LLEU LLEU LLEU LLEU LASN LASN LASN LASN LASN LASN LASN LASN LSER LSER LSER LSER LSER LSER LTRP LTRP LTRP LTRP LTRP LTRP LTRP LTRP LTRP LTRP LTRP LTRP LTRP LTRP LTHR L

158159159159159159159159160160160160160160160160161161161161161161161161162162162162162162163163163163163163163163163163163163163163164

34.66436.20337.25638.64839.72538.67837.50637.84437.37437.55736.15335.47334.08136.36738.46738.15639.60940.58741.87942.02941.51942.65740.73440.31941.25341.35039.96140.03442.40742.43243.19844.37845.65946.12045.51146.27844.47547.22847.31346.02144.20844.94144.15243.75544.639

86.61686.31685.88186.58285.97888.04584.42183.99583.62582.15781.52381.48180.75680.94781.69881.96581.13780.59081.05182.49683.08483.09179.08178.38478.57177.14876.64675.37676.91577.58575.90675.58975.48076.73477.43278.52477.12177.42778.57079.33677.95679.11774.12573.22173.884

4.9786.5245.6235.7574.8725.4385.9037.0234.8634.8904.8876.3866.5417.6703.7472.5934.0963.2583.7713.6422.6654.6103.1764.0432.0161.7501.3390.6810.696-0.2220.8530.1501.0641.5972.6842.9503.5381.2372.0223.9534.5364.659-0.3380.367-1.511

65.6462.8660.5860.3157.6559.0559.7160.1657.4055.8955.1955.0252.8551.5454.2854.4353.4353.4554.8256.8056.5255.2153.5753.4853.9753.6852.1855.0154.0955.2353.7254.5157.0059.3759.9561.2560.8160.4562.4361.4860.9360.5953.8053.9152.58

LLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLL

ONCCCCCONCCCCCCONCCCONCONCCOCONCCCCCCCNCCCCON

CACBOG1CG2CONCACBCGOD1OD2CONCACBCGCDOE1NE2CONCACBCGOD1OD2CONCACBOGCONCACBCGCDCENZC

THR LTHR LTHR LTHR LTHR LTHR LASP LASP LASP LASP LASP LASP LASP LASP LGLN LGLN LGLN LGLN LGLN LGLN LGLN LGLN LGLN LASP LASP LASP LASP LASP LASP LASP LASP LSER LSER LSER LSER LSER LSER LLYS LLYS LLYS LLYS LLYS LLYS LLYS LLYS L

164164164164164164165165165165165165165165166166166166166166166166166167167167167167167167167168168168168168168169169169169169169169169

44.61044.60545.80543.40045.84546.71245.97147.16546.79946.25245.04446.98448.00947.50849.22350.20751.47352.57653.90954.12254.82249.65349.19949.57749.25749.50348.91047.64349.61550.24951.40149.73350.47349.57048.45651.22052.02751.05251.80050.79849.67848.99848.22547.15452.812

72.60372.75073.48373.46271.88072.41970.64969.83768.36067.85567.72567.49770.13570.59569.68869.82569.18469.58869.32668.37770.26469.16268.06369.90169.42170.54270.24870.44269.74268.27568.41467.10965.92664.62765.01266.08065.23167.15867.44867.86766.84966.63865.18165.01568.527

-2.117-3.624-4.091-4.131-1.815-1.359-2.208-1.993-1.999-0.542-0.4110.454-3.161-4.165-3.087-4.145-3.640-4.484-4.010-3.327-4.311-5.444-5.439-6.493-7.799-8.785-10.071-10.035-11.037-8.167-8.028-8.488-9.062-9.158-9.870-10.403-10.659-11.101-12.364-13.469-13.648-15.020-14.949-16.011-12.332

51.8251.2551.2650.5151.9652.0053.0553.4555.5260.0761.0363.3852.5752.0750.8750.4549.0650.0950.8150.7450.1051.4750.4652.1154.3156.8059.4760.7360.3155.0155.2855.8956.8656.6460.8956.3657.5656.3057.5959.3262.1262.5264.2263.9557.97

LLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLL

CCOCCONCCCOOCONCCCCONCONCCCOOCONCCOCONCCCCCNC

ONCACBCGOD1OD2CONCACBOGCONCACBOG1CG2CONCACBCGCD1CE1CD2CE2CZOHCONCACBOGCONCACBCGSD

LYS LASP LASP LASP LASP LASP LASP LASP LASP LSER LSER LSER LSER LSER LSER LTHR LTHR LTHR LTHR LTHR LTHR LTHR LTYR LTYR LTYR LTYR LTYR LTYR LTYR LTYR LTYR LTYR LTYR LTYR LSER LSER LSER LSER LSER LSER LMET LMET LMET LMET LMET L

169170170170170170170170170171171171171171171172172172172172172172173173173173173173173173173173173173174174174174174174175175175175175

53.94652.44653.43852.78851.71051.62250.89653.90154.69453.44654.03855.44055.70853.87654.59652.82652.50752.05250.82352.97851.32950.67251.05149.87850.33451.20952.51753.32950.70351.56452.82753.70348.98749.38747.77846.78945.89846.70945.98445.80745.34944.63745.56445.28845.001

68.20169.78670.86872.12972.75072.39873.58171.14872.06270.33970.45570.03768.79971.86672.18572.58373.87774.80974.38375.07673.74072.68874.80574.93075.30574.18574.15573.24373.17572.13072.16371.12675.98376.94975.89576.95576.57476.56777.30376.54478.46678.93979.64181.03981.374

-12.490-11.987-11.910-12.489-11.564-10.321-12.024-10.435-10.191-9.478-8.108-8.123-8.882-7.423-6.436-7.840-7.362-8.372-8.882-9.669-6.295-6.205-5.587-4.669-3.199-2.606-2.818-2.256-1.858-1.375-1.586-1.149-5.133-5.773-4.636-4.809-6.002-7.154-3.506-2.616-3.501-2.408-1.563-1.2860.591

57.9757.5957.4960.3062.6865.2262.9955.9054.9254.1953.6553.1754.7052.8151.5951.6451.6651.6150.2250.2951.4351.3451.8052.7352.7452.9253.0754.8053.0654.5655.2456.4152.9852.5154.5056.5956.8958.4157.5656.5259.3960.0261.6566.4170.49

LLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLL

ONCCCOOCONCCOCONCCOCCONCCCCCCCCOCONCCOCONCCCS

CECONCACBOGCONCACBOGCONCACBOG1CG2CONCACBCGCD1CD2CONCACBOG1CG2CONCACBCGCD1CD2CO

MET LMET LMET LSER LSER LSER LSER LSER LSER LSER LSER LSER LSER LSER LSER LTHR LTHR LTHR LTHR LTHR LTHR LTHR LLEU LLEU LLEU LLEU LLEU LLEU LLEU LLEU LTHR LTHR LTHR LTHR LTHR LTHR LTHR LLEU LLEU LLEU LLEU LLEU LLEU LLEU LLEU L

175175175176176176176176176177177177177177177178178178178178178178179179179179179179179179180180180180180180180181181181181181181181181

46.27143.56743.68042.43341.30940.17839.20840.96441.06340.65940.19341.14340.94038.88938.61937.97036.56235.59435.76334.14636.12736.17235.82035.32136.06735.52735.69436.18733.80833.32833.07831.62231.12631.69129.60531.08831.29830.41229.91830.34731.84532.15432.73628.38127.828

81.68179.79580.54179.63080.50279.71280.59481.31080.73982.61683.44084.49785.20884.05684.63583.90684.39183.26082.54183.76285.36485.05786.60687.64188.94290.14189.99091.46287.79288.19487.36987.39386.06684.98185.99688.53688.59489.50590.67691.92691.90292.71392.47890.60589.535

0.823-2.863-3.860-2.237-2.491-2.851-2.947-1.208-0.089-1.358-0.268-0.0051.304-0.493-1.5840.4530.3110.267-0.937-0.0461.5302.6811.1892.0731.7692.5474.0592.1511.8720.8202.9122.8873.4602.7123.3783.7484.9513.1033.8463.0522.6851.4193.7914.0164.105

66.5059.2959.3758.8159.1057.8860.6958.4857.9957.2057.9656.5955.0659.6760.6760.9361.5760.5862.4961.1462.3661.8464.0265.7666.0166.6365.1066.8166.3066.8867.9370.6670.3671.9371.2971.7871.4974.2076.8975.9676.5676.5075.7478.7880.37

LLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLL

CCONCCOCONCCOCONCCOCCONCCCCCCONCCOCCONCCCCCCO

440744084409441044114412441344144415441644174418441944204421442244234424442544264427442844294430443144324433443444354436443744384439444044414442444344444445444644474448444944504451

NCACBOG1CG2CONCACBCGCDCENZCONCACBCGOD1OD2CONCACBCGCDOE1OE2CONCACBCGCD1CE1CD2CE2CZOHCO

THR LTHR LTHR LTHR LTHR LTHR LTHR LLYS LLYS LLYS LLYS LLYS LLYS LLYS LLYS LLYS LASP LASP LASP LASP LASP LASP LASP LASP LGLU LGLU LGLU LGLU LGLU LGLU LGLU LGLU LGLU LTYR LTYR LTYR LTYR LTYR LTYR LTYR LTYR LTYR LTYR LTYR LTYR L

182182182182182182182183183183183183183183183183184184184184184184184184185185185185185185185185185186186186186186186186186186186186186

27.73526.28925.66226.67425.24026.23727.00225.40625.73725.01923.49923.06521.65721.48525.60226.17324.87124.50023.53623.42023.08123.48425.75625.88826.69628.03528.56229.99330.85531.32230.88628.94229.75028.79429.50228.92529.43130.78431.30028.58729.09430.43930.92329.29030.217

91.78691.91592.61593.43391.51492.85693.77492.65893.59493.19793.32293.99593.78594.81195.05696.02495.15896.43796.16097.34998.44097.12597.17798.39196.40396.85295.83995.38796.05095.36397.27796.88897.78195.84795.88894.79994.92495.12794.99094.60694.47294.66994.67097.25898.023

4.1453.8585.0775.7286.0822.6682.6221.6440.562-0.749-0.752-2.073-2.691-3.7431.0410.5082.1672.7213.8974.8514.3866.0593.1332.9983.6854.0085.0234.7885.8306.7305.8472.7602.5731.9060.600-0.320-1.735-1.986-3.274-2.809-4.091-4.334-5.639-0.011-0.236

80.9582.3382.1381.8582.0483.7084.9184.6886.0086.7286.5487.4788.1089.0286.0886.3885.8185.7987.5989.9390.9991.1184.8685.1183.3682.2082.0882.9883.9285.4583.5180.9379.3180.6881.1979.7479.6779.5178.7579.1378.3177.8777.8981.4482.62

LLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLL

NCCOCCONCCCCCNCONCCCOOCONCCCCOOCONCCCCCCCCOCO

445244534454445544564457445844594460446144624463446444654466446744684469447044714472447344744475447644774478447944804481448244834484448544864487448844894490449144924493449444954496

NCACBCGCDOE1OE2CONCACBCGCDNECZNH1NH2CONCACBCGCD2ND1CE1NE2CONCACBCGOD1ND2CONCACBOGCON

GLU LGLU LGLU LGLU LGLU LGLU LGLU LGLU LGLU LARG LARG LARG LARG LARG LARG LARG LARG LARG LARG LARG LHIS LHIS LHIS LHIS LHIS LHIS LHIS LHIS LHIS LHIS LASN LASN LASN LASN LASN LASN LASN LASN LSER LSER LSER LSER LSER LSER LTYR L

187187187187187187187187187188188188188188188188188188188188189189189189189189189189189189190190190190190190190190191191191191191191192

28.00427.59626.08225.56724.10523.36323.70627.99327.54328.80029.10528.94527.47127.28627.40826.28125.10926.35730.49330.83431.15932.50533.45033.20232.18434.05633.56832.44732.56731.86633.49533.51133.49733.35932.58234.14934.74934.73335.88637.23138.29239.56737.56137.61137.721

97.58098.76898.74797.88998.19897.30599.319100.113101.169100.085101.364101.227101.291101.669100.48499.818100.22698.738101.898103.050100.835101.005100.127100.34499.803101.028100.890100.160100.59599.713101.241101.062102.448102.314101.514103.133100.29299.519100.55699.902100.968100.44298.59398.63097.469

-0.242-0.987-1.066-2.208-2.392-2.767-2.073-0.356-0.7840.7151.3472.8643.2814.7565.6125.9325.4776.7160.9731.2080.491-0.0240.7932.2593.0493.0624.3064.329-1.488-1.942-2.203-3.644-4.284-5.777-6.291-6.492-4.083-5.032-3.430-3.668-3.415-3.635-2.756-1.534-3.426

81.2181.6382.2283.9885.0084.7086.0680.6680.6979.9079.4480.3782.7185.0685.9386.7086.6686.3778.2879.4276.8175.7776.1875.8375.7976.3376.2376.3074.2673.3273.2272.2872.2772.2272.4572.2771.8671.8270.4869.3068.0870.3768.6768.7467.14

LLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLL

NCCCCOOCONCCCCNCNNCONCCCCNCNCONCCCONCONCCOCON

449744984499450045014502450345044505450645074508450945104511451245134514451545164517451845194520452145224523452445254526452745284529453045314532453345344535453645374538453945404541

CACBCGCD1CE1CD2CE2CZOHCONCACBOG1CG2CONCACOCBSGNCACBCGCDOE1OE2CONCACBCONCACBOG1CG2CO

TYR LTYR LTYR LTYR LTYR LTYR LTYR LTYR LTYR LTYR LTYR LTHR LTHR LTHR LTHR LTHR LTHR LTHR LCYS LCYS LCYS LCYS LCYS LCYS LGLU LGLU LGLU LGLU LGLU LGLU LGLU LGLU LGLU LALA LALA LALA LALA LALA LTHR LTHR LTHR LTHR LTHR LTHR LTHR L

192192192192192192192192192192192193193193193193193193194194194194194194195195195195195195195195195196196196196196197197197197197197197

37.94536.80935.57734.69033.53235.35034.19233.29932.17639.23939.40540.18241.44442.46542.31743.90341.94341.74142.58843.22044.75045.36742.75443.25345.47546.94047.31347.26648.02148.87647.71347.67647.53048.63149.25149.14650.64451.39451.00852.38952.65252.33654.09153.02452.745

96.13395.19195.51796.49896.85095.01595.42496.34696.79795.60995.51095.36794.83395.89896.82995.30093.53193.34392.68691.40491.50191.72590.30388.66291.10191.29492.45793.90494.91694.56096.09890.06589.60489.61188.30987.58488.50289.09688.03188.02488.66590.04788.66086.70285.779

-2.841-3.337-2.560-3.018-2.250-1.281-O.452-O.960-0.300-3.407-4.664-2.565-2.979-2.780-3.840-2.971-2.280-1.075-3.059-2.686-2.683-3.717-3.656-3.082-1.654-1.514-0.485-1.015-0.1470.691-0.294-1.0280.172-1.891-1.699-2.984-1.252-1.899-0.0640.2521.5761.4341.8790.0700.788

1.001.001.001.001.001.001.001.001.001.001.001.001.001.001.001.001.001.001.001.OO1.001.001.OO1.001.001.001.001.001.001.001.001.OO1.001.001.OO1.001.001.001.001.001.001.001.001.001.00

66.1864.9865.0665.7665.5264.4464.8365.2565.9365.7565.7064.2563.3163.1163.0662.6963.3661.6763.7664.6264.5664.2765.8469.2765.4966.3767.9270.1472.4674.0374.4466.0066.5765.2864.1263.4464.1363.4264.8264.0963.7264.0663.1564.0264.77

LLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLL

CCCCCCCCOCONCCOCCONCCOCSNCCCCOOCONCCCONCCOCCO

454245434544454545464547454845494550455145524553455445554556455745584559456045614562456345644565456645674568456945704571457245734574457545764577457845794580458145824583458445854586

NCACBCGCD2ND1CE1NE2CONCACBCGCDCENZCONCACBOG1CG2CONCACBOGCONCACBOG1CG2CONCACBOGCO

HIS LHIS LHIS LHIS LHIS LHIS LHIS LHIS LHIS LHIS LLYS LLYS LLYS LLYS LLYS LLYS LLYS LLYS LLYS LTHR LTHR LTHR LTHR LTHR LTHR LTHR LSER LSER LSER LSER LSER LSER LTHR LTHR LTHR LTHR LTHR LTHR LTHR LSER LSER LSER LSER LSER LSER L

198198198198198198198198198198199199199199199199199199199200200200200200200200201201201201201201202202202202202202202203203203203203203

53.91254.76454.20954.60054.01255.73455.82354.82156.29156.74757.04858.58659.15260.16560.61462.15762.45959.21560.31658.53458.88957.82356.49257.96558.93759.28758.55258.50357.27057.31758.53257.82459.38959.57960.78961.00162.05158.38458.24957.50956.35156.53656.84055.10955.060

86.65785.47784.82183.39482.22683.03581.69781.19085.71786.72084.69384.70883.32682.57981.34381.07179.58785.03785.43984.77085.15184.59984.77583.10386.65687.16687.42788.87889.28490.61789.67889.37990.67991.60992.51492.70091.77092.49293.07892.62093.39794.78894.69892.57491.850

-0.910-1.189-2.512-2.645-2.233-3.297-3.331-2.634-1.302-1.785-1.083-1.161-0.608-1.411-0.633-0.720-1.216-2.499-2.483-3.606-4.867-5.955-5.459-6.030-5.003-6.033-4.027-4.257-5.062-5.277-2.932-2.026-2.903-1.731-1.942-3.363-1.502-1.483-0.433-2.445-2.139-2.770-4.173-2.642-3.730

62.8461.6959.7759.1058.4659.0857.6157.6261.0360.8860.8661.4862.5565.3167.9868.9872.5860.7159.1561.3462.4161.9861.4861.9663.5563.6365.0866.7766.6769.8167.8967.6368.9970.4070.2171.6169.3271.8173.0672.0872.5172.6173.8973.1573.17

LLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLL

NCCCCNCNCONCCCCCNCONCCOCCONCCOCONCCOCCONCCOCO

458745884589459045914592459345944595459645974598459946004601460246034604460546064607460846094610461146124613461446154616461746184619462046214622462346244625462646274628462946304631

NCDCACBCGCONCACBCG2CG1CD1CONCACBCG1CG2CONCACBCGCDCENZCONCACBOGCONCACBCGCD1CD2CE1CE2

PRO LPRO LPRO LPRO LPRO LPRO LPRO LILE LILE LILE LILE LILE LILE LILE LILE LVAL LVAL LVAL LVAL LVAL LVAL LVAL LLYS LLYS LLYS LLYS LLYS LLYS LLYS LLYS LLYS LSER LSER LSER LSER LSER LSER LPHE LPHE LPHE LPHE LPHE LPHE LPHE LPHE L

204204204204204204204205205205205205205205205206206206206206206206207207207207207207207207207208208208208208208209209209209209209209209

54.02053.82252.76451.76052.46652.31952.55051.53050.94751.13150.84750.08850.32849.49249.11248.71547.51347.69748.95247.69946.64447.07145.44244.29243.87844.99645.03046.33645.76443.09642.82742.40641.41341.92243.12540.27840.32839.22538.20237.39236.44235.28836.65034.32135.650

92.80993.78692.15792.89194.17192.27693.25491.34591.53090.29789.20190.13988.97791.85091.67292.49193.12294.63494.81295.65093.21193.73892.67492.81291.40190.73691.28990.84790.11793.54393.34194.35595.21396.63696.63895.35094.99095.93096.36995.23294.76095.39693.56894.89693.051

-1.971-0.890-2.391-1.538-1.377-3.827-4.516-4.270-5.602-6.391-5.470-7.496-8.411-5.266-4.177-6.123-5.663-5.144-4.282-6.301-6.846-7.786-6.741-7.622-8.024-8.978-10.379-11.268-12.435-6.906-5.709-7.676-7.140-6.816-6.088-8.117-9.309-7.600-8.515-8.946-7.934-7.710-7.240-6.848-6.385

73.5273.6873.3772.8373.1073.8273.6574.1575.2175.7377.3575.8176.3675.5376.2675.0874.7174.4073.3074.3874.8875.8774.5874.3574.5075.1976.5377.7779.3074.4573.7674.3474.6774.2675.0475.1275.0775.8976.6875.7176.2176.2776.9576.6276.70

LLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLL

NCCCCCONCCCCCCONCCCCCONCCCCCNCONCCOCONCCCCCCC

463246334634463546364637463846394640464146424643464446454646464746484649465046514652465346544655465646574658465946604661466246634664466546664667466846694670467146724673467446754676

CZCONCACBCGOD1ND2CONCACBCGCDNECZNH1NH2CONCACBCGOD1ND2CONCACBCGCDOE1OE2COOXTCBCONCA

PHE LPHE LPHE LASN LASN LASN LASN LASN LASN LASN LASN LARG LARG LARG LARG LARG LARG LARG LARG LARG LARG LARG LASN LASN LASN LASN LASN LASN LASN LASN LGLU LGLU LGLU LGLU LGLU LGLU LGLU LGLU LGLU LGLU LALA HALA HALA HALA HALA H

20920920921021021021021021021021021121121121121121121121121121121121221221221221221221221221321321321321321321321321321311111

34.49937.34337.38036.55435.66636.05337.16837.28538.00734.27233.97733.42232.09131.30331.27929.97529.66328.65327.68028.57631.24030.29831.60931.02231.28732.72733.70632.81031.45130.83832.52332.87931.66930.70829.29329.14828.31134.05235.00534.01039.94539.24038.01439.64740.167

93.76097.34697.40398.03899.132100.417101.090100.936101.84098.73298.37398.70898.26797.73798.47398.23599.546100.28999.841101.48499.21098.696100.529101.615103.060103.685102.985105.038101.449102.032100.64799.81599.38498.31798.28798.66397.881100.491101.056100.45147.05845.31145.28344.57745.578

-6.215-7.803-6.577-8.608-8.158-8.857-8.158-6.984-8.855-8.427-9.515-7.429-7.731-6.518-5.284-4.336-3.767-4.194-4.984-3.765-8.590-9.159-8.707-9.578-8.990-9.302-9.365-9.430-11.064-11.978-11.235-12.407-13.335-12.739-13.389-14.613-12.696-13.158-12.555-14.407-15.210-13.489-13.595-15.546-14.643

77.3077.2176.6078.7781.0280.7181.3681.9582.0182.3482.1384.6787.9388.2188.7489.2089.8789.8890.5490.6090.2390.5992.9295.3095.6295.9896.5795.8697.0497.8498.65100.44101.37103.86105.73106.92106.19101.34101.24102.5057.5956.4156.0358.2457.67

LLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLLHHHHH

CCONCCCONCONCCCCNCNNCONCCCONCONCCCCOOCOOCCONC

467746784679468046814682468346844685468646874688468946904691469246934694469546964697469846994700470147024703470447054706470747084709471047114712471347144715471647174718471947204721

NCACBCG1CG2CONCACBCGCDCENZCONCACBCGCD1CD2CONCACBCG1CG2CONCACBCGCDOE1OE2CONCACBOGC

VAL HVAL HVAL HVAL HVAL HVAL HVAL HLYS HLYS HLYS HLYS HLYS HLYS HLYS HLYS HLYS HLEU HLEU HLEU HLEU HLEU HLEU HLEU HLEU HVAL HVAL HVAL HVAL HVAL HVAL HVAL HGLU HGLU HGLU HGLU HGLU HGLU HGLU HGLU HGLU HSER HSER HSER HSER HSER H

222222233333333344444444555555566666666677777

39.81238.98239.84738.90040.56238.20838.75336.97936.21435.31335.97434.98835.87835.29635.35534.71635.27134.43735.30136.23737.06835.26533.76834.44332.46631.68030.89230.08031.85930.74229.72231.05830.24131.12032.41033.63433.45434.77829.00529.00627.94926.78425.87025.35126.041

45.19845.07244.75044.73043.23246.29047.33246.19047.34247.86248.25648.69848.93948.15647.20646.22348.27348.25548.00946.87846.74845.68649.50450.51049.49450.75450.95552.25750.91950.82450.17551.69551.84452.54251.72052.07052.59451.77252.67453.58752.40953.22852.85051.64853.138

-12.287-11.168-9.932-8.646-10.087-10.890-10.978-10.426-10.003-11.046-12.313-13.499-14.898-16.087-8.701-8.522-7.924-6.746-5.477-5.386-3.950-5.471-6.651-6.706-6.457-6.411-7.693-7.619-8.930-5.191-5.154-4.269-3.056-2.043-1.614-2.427-3.591-1.950-3.334-4.190-2.617-2.628-3.832-3.702-1.335

55.9755.8055.1653.6854.6755.9656.1355.2154.6056.9361.0964.1666.4769.3052.8953.6150.6549.5246.6747.9344.5045.1449.5749.9348.5848.5148.3547.3146.3948.9149.4849.7750.8750.5252.9754.9356.2453.2451.9253.2052.2852.1551.1452.3152.74

HHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH

NCCCCCONCCCCCNCONCCCCCCONCCCCCONCCCCOOCONCCOC

472247234724472547264727472847294730473147324733473447354736473747384739474047414742474347444745474647474748474947504751475247534754475547564757475847594760476147624763476447654766

ONCACONCACONCACONCACBCGCD1CD2CONCACBCG1CG2CONCACBCGCDCENZCONCDCACBCGCON

SER HGLY HGLY HGLY HGLY HGLY HGLY HGLY HGLY HGLY HGLY HGLY HGLY HLEU HLEU HLEU HLEU HLEU HLEU HLEU HLEU HVAL HVAL HVAL HVAL HVAL HVAL HVAL HLYS HLYS HLYS HLYS HLYS HLYS HLYS HLYS HLYS HPRO HPRO HPRO HPRO HPRO HPRO HPRO HGLY H

788889999101010101111111111111111121212121212121313131313131313131414141414141415

26.40724.92624.15624.57123.98825.54926.02325.09424.39525.09624.49224.45825.26923.49123.32422.67022.21723.39921.63422.42221.36622.71821.70822.07723.56821.16121.77422.69720.83420.86719.41918.77917.76317.03616.29121.48121.44122.04222.31822.62622.99523.12221.66620.57021.993

52.35653.90853.92254.96255.13655.68556.60557.86358.19058.58959.89160.32259.94861.15861.73763.09563.87464.04065.21860.91260.53260.66859.92158.48758.24657.69560.47361.15860.19560.75661.03462.22963.06464.15463.24459.88858.72460.41161.86959.54860.55561.87758.51758.93357.257

-0.512-1.1760.0641.1062.3120.7551.7971.9260.9853.0543.0994.5395.4014.8296.1725.9717.2158.1056.6747.0216.6038.2448.9638.9299.4479.90310.35310.64911.25012.64613.13012.31113.15412.22911.29013.67313.54614.75214.89115.80216.94716.19116.30516.72816.354

52.3553.9153.3554.5254.6454.0655.8556.9758.2156.9356.3057.2256.3757.8858.3357.2857.4156.5955.3358.5359.2258.8459.9560.7560.5660.6260.4960.6560.4259.4660.9863.1765.6268.2671.0758.3358.3157.0755.7556.2856.5356.4155.9256.8855.44

HHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH

ONCCONCCONCCONCCCCCCONCCCCCONCCCCCNCONCCCCCON

476747684769477047714772477347744775477647774778477947804781478247834784478547864787478847894790479147924793479447954796479747984799480048014802480348044805480648074808480948104811

CACONCACONCACBOGCONCACBCGCD1CD2CONCACBCGCDCENZCONCACBCGCD1CD2CONCACBOGCON

GLY HGLY HGLY HGLY HGLY HGLY HGLY HSER HSER HSER HSER HSER HSER HLEU HLEU HLEU HLEU HLEU HLEU HLEU HLEU HLYS HLYS HLYS HLYS HLYS HLYS HLYS HLYS HLYS HLEU HLEU HLEU HLEU HLEU HLEU HLEU HLEU HSER HSER HSER HSER HSER HSER HCYS H

151515161616161717171717171818181818181818191919191919191919202020202020202021212121212122

20.99420.48419.89220.69919.95120.77321.72920.29720.77419.76220.09220.92020.16321.93822.07222.94823.14221.89624.21222.77423.62422.50923.14022.06022.45321.23221.66320.77123.87123.23225.19625.95727.36127.43928.97926.68226.05825.99926.44626.57825.23024.93127.72728.30728.244

56.24155.49554.47656.03855.54354.49453.97054.04252.84551.72951.11153.09153.85352.50552.69953.92654.45855.21655.42351.41250.71751.14050.02248.99047.67046.61545.11444.17150.39250.88350.05950.33450.73351.80952.10353.09649.09247.92649.28148.19947.95248.98348.49849.64247.418

16.72415.46515.54414.26313.10112.48213.14511.30710.68710.75212.0209.2138.6858.6217.1696.9555.5725.0785.6016.6237.3745.3534.8214.5813.7433.8284.2375.2263.5112.4743.5042.2582.7493.8404.1143.4071.3421.8170.097-0.700-1.286-2.110-1.651-1.707-2.228

54.8854.2054.7453.1451.8652.0051.5953.1154.4554.7059.6354.4053.4454.0054.7354.7056.4356.2756.4455.3856.0053.5253.5556.2758.9961.9363.6465.4852.3550.7250.3949.1147.8947.6043.1443.0848.7648.5047.5349.8049.0053.2850.2651.2650.61

HHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH

CCONCCONCCOCONCCCCCCONCCCCCNCONCCCCCCONCCOCON

481248134814481548164817481848194820482148224823482448254826482748284829483048314832483348344835483648374838483948404841484248434844484548464847484848494850485148524853485448554856

CACOCBSGNCACBCONCACBCONCACBOGCONCACONCACBCGCD1CD2CE1CE2CZCONCACBOG1CG2CONCA

CYS HCYS HCYS HCYS HCYS HALA HALA HALA HALA HALA HALA HALA HALA HALA HALA HSER HSER HSER HSER HSER HSER HGLY HGLY HGLY HGLY HPHE HPHE HPHE HPHE HPHE HPHE HPHE HPHE HPHE HPHE HPHE HTHR HTHR HTHR HTHR HTHR HTHR HTHR HPHE HPHE H

222222222223232323232424242424252525252525262626262727272727272727272727282828282828282929

29.41229.34629.35730.76132.24229.41529.30228.61430.60431.27730.91132.20732.73132.14331.35133.30233.43832.64533.28734.88935.87435.13336.53337.33238.40536.71537.35738.31737.57937.32637.11936.66736.36636.13436.33635.18536.74835.81336.20235.40337.40235.51436.11534.52434.149

47.53146.50345.32247.35247.17546.99346.23447.10845.93546.78744.67644.28543.14043.71842.91943.76643.14744.05545.34543.03843.63742.20442.08541.02040.86740.20539.13639.69940.29239.51241.53240.05942.14241.42538.07238.30736.82035.89334.43433.36234.18836.10235.56836.87437.342

-3.065-4.180-3.900-2.238-3.280-5.373-6.577-7.567-7.103-7.604-7.200-7.697-6.924-9.135-9.301-9.816-11.075-12.109-12.458-11.463-10.835-12.453-12.885-12.147-12.358-11.356-10.671-9.644-8.414-7.245-8.474-6.196-7.299-6.272-10.076-9.844-9.877-9.410-9.933-9.243-9.641-7.818-6.977-7.593-6.286

50.7750.5550.9851.7154.1349.8949.0347.9949.6951.4349.1448.4747.0048.3449.2246.9445.8845.8845.3445.4143.9545.4244.7845.6447.5745.5846.0843.8743.8840.5042.6742.2844.4642.6547.0849.1648.3550.1252.1456.5553.8349.2149.7947.7247.97

HHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH

CCOCSNCCCONCCCONCCOCONCCONCCCCCCCCCONCCOCCONC

485748584859486048614862486348644865486648674868486948704871487248734874487548764877487848794880488148824883488448854886488748884889489048914892489348944895489648974898489949004901

CBCGCD1CD2CE1CE2CZCONCACBCG2CG1CD1CONCACBOGCONCACBCGCD1CE1CD2CE2CZOHCONCACBCONCACBCGSD

PHE HPHE HPHE HPHE HPHE HPHE HPHE HPHE HPHE HILE HILE HILE HILE HILE HILE HILE HILE HSER HSER HSER HSER HSER HSER HTYR HTYR HTYR HTYR HTYR HTYR HTYR HTYR HTYR HTYR HTYR HTYR HALA HALA HALA HALA HALA HMET HMET HMET HMET HMET H

292929292929292929303030303030303031313131313132323232323232323232323233333333333434343434

32.78732.17232.70931.02732.19330.51931.06934.06634.65033.41633.24032.43931.08533.25132.53334.51034.42635.63936.87937.82737.51937.60838.52837.25837.97538.21339.25138.92239.84740.59041.53041.05141.96237.21635.94937.93537.40038.33637.32838.02936.47436.18634.86934.69635.784

38.13238.69139.71838.14440.29238.68339.87536.25536.40535.16134.13432.94233.45032.35831.00033.60733.07833.64933.12532.85731.56934.04133.58235.34936.32237.56837.37636.93936.71337.59337.45536.93736.80036.75036.96036.90037.57437.42439.12139.56339.86641.22541.29240.62941.463

-6.445-5.220-4.625-4.646-3.574-3.472-3.036-5.324-4.308-5.640-4.657-5.181-5.918-6.337-6.629-4.067-2.972-4.781-4.259-5.438-6.102-3.249-2.645-3.166-2.352-3.172-4.152-5.514-6.359-3.856-4.906-6.187-7.206-1.113-1.073-0.1011.2102.2470.848-0.0261.4811.2220.611-0.882-1.994

47.1449.2048.9250.3249.5351.6050.3648.2547.8748.0548.9551.2551.5053.6756.7747.1046.7245.7446.3445.2747.3447.4248.5146.5245.4945.2947.5846.7247.2247.3949.7149.3950.6444.5343.2642.8742.6340.2141.9841.3441.2040.6339.1039.7745.71

HHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH

CCCCCCCCONCCCCCCONCCOCONCCCCCCCCOCONCCCONCCCS

490249034904490549064907490849094910491149124913491449154916491749184919492049214922492349244925492649274928492949304931493249334934493549364937493849394940494149424943494449454946

CECONCACBOGCONCACBCGCD2CE2CE3CD1NE1CZ2CZ3CH2CONCACBCG1CG2CONCACBCGCDNECZNH1NH2CONCACBCG

MET HMET HMET HSER HSER HSER HSER HSER HSER HTRP HTRP HTRP HTRP HTRP HTRP HTRP HTRP HTRP HTRP HTRP HTRP HTRP HTRP HVAL HVAL HVAL HVAL HVAL HVAL HVAL HARG HARG HARG HARG HARG HARG HARG HARG HARG HARG HARG HGLN HGLN HGLN HGLN H

343434353535353535363636363636363636363636363637373737373737383838383838383838383839393939

34.88636.06435.79236.21536.20037.67038.36435.69535.72035.27835.09233.73232.75732.19131.21032.31332.18431.19930.34331.53830.54236.26336.74336.70937.67739.03640.07139.66337.19936.99537.22836.76935.66936.08434.80335.17034.23132.92634.63837.85938.90337.66138.67339.30840.465

42.98241.97141.35743.28544.08044.28043.03645.45546.06246.06547.56947.83747.46348.14147.28549.38846.21146.15247.66949.74648.88948.22647.75049.36250.16150.10951.09148.67651.59552.08952.30453.75553.85653.72553.78553.62353.60653.65453.48754.74554.40855.97956.94857.43058.409

-1.9642.6283.6242.6103.8294.1244.4543.6732.5684.8024.8465.3844.5763.4762.8872.9674.5643.6211.8411.8661.3005.5526.6565.0495.8175.1445.8765.1065.7224.6306.8336.8127.9399.18610.02511.37212.43712.24713.6757.1867.6226.8306.9265.5705.662

37.9241.2041.8541.1142.0043.0547.7941.7141.4742.0440.9140.2043.6243.8045.5744.8944.5844.9346.0647.8747.6841.1641.6541.5441.7242.3739.8538.4743.0142.6644.3244.7245.5045.7945.9945.0947.2445.9645.7145.9845.2447.0447.0646.4347.08

HHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH

CCONCCOCONCCCCCCCNCCCCONCCCCCONCCCCNCNNCONCCC

494749484949495049514952495349544955495649574958495949604961496249634964496549664967496849694970497149724973497449754976497749784979498049814982498349844985498649874988498949904991

CDOE1NE2CONCACBOG1CG2CONCDCACBCGCONCACBCGCDOE1OE2CONCACBCONCACBCGCDNECZNH1NH2CON

GLN HGLN HGLN HGLN HGLN HTHR HTHR HTHR HTHR HTHR HTHR HTHR HPRO HPRO HPRO HPRO HPRO HPRO HPRO HGLU HGLU HGLU HGLU HGLU HGLU HGLU HGLU HGLU HALA HALA HALA HALA HALA HARG HARG HARG HARG HARG HARG HARG HARG HARG HARG HARG HLEU H

393939393940404040404040414141414141414242424242424242424343434343444444444444444444444445

41.33040.83542.76137.95637.11438.51437.84138.30139.70738.31838.24639.05937.56436.29537.89036.82335.63939.30339.84639.83841.21041.53240.59639.07938.70738.25242.07343.24041.52742.34743.34843.01843.68942.57042.88942.93844.32144.77345.69246.98747.68947.59342.07340.89842.750

58.53258.57558.61558.11558.73958.59359.68659.72260.03058.47060.98561.01362.06162.11563.38264.32163.43863.78164.51863.39963.66563.33964.03963.41662.25163.97962.70962.73561.85361.08261.92859.83059.13659.38958.03257.88558.81358.72557.57157.60558.78956.43056.93856.96455.849

4.5183.3414.7927.6016.9198.6609.46810.85110.77211.4298.9028.0389.29610.0738.7009.3709.5549.0258.26510.18410.52712.03113.17913.16313.75812.3239.6289.7428.7577.7066.8158.3527.6999.5729.83911.29611.78013.29013.54413.92114.06114.1549.2269.4368.788

47.3545.8345.7747.5647.3048.2450.7350.7652.7051.2051.3651.1052.2152.2451.0151.1450.9651.2751.3450.9152.3055.5859.6662.6063.3864.1251.8152.6549.4448.6347.3748.3348.6047.4948.9052.0959.2862.1164.3063.2863.1363.8447.2747.7444.62

HHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH

CONCONCCOCCONCCCCCONCCCCOOCONCCCONCCCCNCNNCON

499249934994499549964997499849995000500150025003500450055006500750085009501050115012501350145015501650175018501950205021502250235024502550265027502850295030503150325033503450355036

CACBCGCD1CD2CONCACBCGCDOE1OE2CONCACBCGCD2CE2CE3CD1NE1CZ2CZ3CH2CONCACBCG1CG2CONCACBCONCACB

LEU HLEU HLEU HLEU HLEU HLEU HLEU HGLU HGLU HGLU HGLU HGLU HGLU HGLU HGLU HGLU HTRP HTRP HTRP HTRP HTRP HTRP HTRP HTRP HTRP HTRP HTRP HTRP HTRP HTRP HVAL HVAL HVAL HVAL HVAL HVAL HVAL HALA HALA HALA HALA HALA HSER HSER HSER H

454545454545454646464646464646464747474747474747474747474747484848484848484949494949505050

42.20142.97943.19044.34442.02041.89042.78440.65340.40539.65438.95337.94537.47837.78839.65138.66740.17539.46640.34039.69439.35638.66839.55639.19938.62438.16639.02538.53438.17838.08937.13835.77834.90933.52435.31735.15034.36435.43034.93433.39335.44735.92335.41635.82437.267

54.62153.92754.95854.45354.76953.72553.29753.24352.10452.73351.75452.32453.51551.55550.91551.05849.72948.45047.26345.99345.04144.02844.95245.53644.34142.94643.89442.75348.29048.49648.04348.05449.05648.93150.43446.59446.26445.78844.43944.44343.65344.12442.37441.42240.907

8.4747.4276.1265.2415.3659.68010.5069.61610.57211.79312.66713.60813.32514.6499.8509.1769.9659.5729.8959.68210.6449.98312.1138.4528.63610.62612.76611.97210.22811.4289.4689.9619.0979.2439.5199.91910.7428.9129.0139.0477.8356.7508.0726.9647.351

43.2141.3741.0839.0141.2844.4142.3144.3546.7848.4352.6256.0857.2655.1946.7146.4446.1846.2645.6049.0449.1548.8249.5047.7848.1749.2950.4649.9645.5146.1845.2146.9446.3946.0046.5547.7448.0147.8847.1247.1346.5246.4945.9745.9745.68

HHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH

CCCCCCONCCCCOOCONCCCCCCCNCCCCONCCCCCONCCCONCC

503750385039504050415042504350445045504650475048504950505051505250535054505550565057505850595060506150625063506450655066506750685069507050715072507350745075507650775078507950805081

OGCONCACBCG2CG1CD1CONCACBOGCONCACBOGCONCACONCACONCACBCGOD1ND2CONCACBOG1CG2C

SER HSER HSER HILE HILE HILE HILE HILE HILE HILE HILE HSER HSER HSER HSER HSER HSER HSER HSER HSER HSER HSER HSER HGLY HGLY HGLY HGLY HGLY HGLY HGLY HGLY HASN HASN HASN HASN HASN HASN HASN HASN HTHR HTHR HTHR HTHR HTHR HTHR H

505050515151515151515152525252525253535353535354545454555555555656565656565656575757575757

38.11034.84234.22434.74034.06132.64732.70331.81130.24034.88135.40335.14735.93836.36835.23135.14733.92635.86535.20936.16836.77034.18533.09234.40333.54032.45431.66432.32631.28131.65330.82932.90133.24134.64134.84835.94833.93233.32833.75632.94532.81731.41930.92430.39433.855

41.99140.23739.83939.57438.32138.54539.31037.23937.45637.44138.00236.12635.25434.01033.30434.67434.91833.88433.37532.72331.61032.33232.14031.91230.92531.43230.68332.71233.27933.59234.05333.39033.81333.31131.70731.26530.94435.34935.99335.94037.32737.83837.62537.33737.740

7.1726.9057.9645.7465.5754.8973.4714.8244.6664.6403.5965.0744.2775.0345.4853.0192.8752.2010.894-0.0410.6861.4480.8802.6473.2204.0404.6144.1725.1256.6037.4017.0428.3768.6868.6748.2599.2028.4887.5369.6519.81710.15811.5959.24910.893

46.9045.9546.2344.3543.4142.3740.1641.8441.5944.6344.4244.4747.0946.8447.8547.4945.9949.0549.6749.0050.0150.7351.0751.0352.2353.8454.9853.9255.9356.9059.0856.9756.8758.5760.8062.9158.8856.1756.0655.5153.5953.4852.4851.2553.43

HHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH

OCONCCCCCCONCCOCONCCOCONCCONCCONCCCONCONCCOCC

508250835084508550865087508850895090509150925093509450955096509750985099510051015102510351045105510651075108510951105111511251135114511551165117511851195120512151225123512451255126

ONCACBCGCD1CE1CD2CE2CZOHCONCACBCGCD1CE1CD2CE2CZOHCONCDCACBCGCONCACBCGOD1OD2CONCACBOGC

THR HTYR HTYR HTYR HTYR HTYR HTYR HTYR HTYR HTYR HTYR HTYR HTYR HTYR HTYR HTYR HTYR HTYR HTYR HTYR HTYR HTYR HTYR HTYR HTYR HPRO HPRO HPRO HPRO HPRO HPRO HPRO HASP HASP HASP HASP HASP HASP HASP HASP HSER HSER HSER HSER HSER H

575858585858585858585858585959595959595959595959596060606060606061616161616161616262626262

34.06234.45335.39836.72537.05936.70137.01337.86838.22937.74838.05835.24435.05635.26734.99033.53832.41831.79130.86731.99731.04930.49429.43735.87336.17036.30135.94836.97937.61936.55035.90834.75336.34235.40536.20636.53837.40335.80434.65533.54535.10234.54335.63835.88933.163

37.06338.88739.39839.19437.85037.42036.25737.01435.74135.42534.22140.92641.67141.32542.74543.01842.55541.33540.83343.32342.82241.54141.02143.28542.52844.57845.62745.18546.48146.88345.65145.91245.82046.21446.27544.90244.61144.02647.50747.56948.38149.67650.51650.04649.619

11.88310.71311.66811.14510.7269.5049.09911.53311.0709.7909.34411.93510.97513.18213.52314.08313.08113.23112.40512.07211.16611.35310.58714.58215.50114.54013.54715.73315.12314.12216.79216.52718.00019.16120.45220.88521.71120.42019.05419.54718.16217.99317.19215.79817.362

52.4152.6752.7652.4953.5253.5453.1153.3954.3854.3554.8553.0453.4452.5152.9552.9055.0054.8954.8054.6855.8155.9156.1852.1452.6151.1050.3251.2950.6149.5052.2051.3853.4754.7755.4657.7758.3058.8354.6554.7454.8256.3257.3959.7856.10

HHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH

ONCCCCCCCCOCONCCCCCCCCOCONCCCCCONCCCOOCONCCOC

512751285129513051315132513351345135513651375138513951405141514251435144514551465147514851495150515151525153515451555156515751585159516051615162516351645165516651675168516951705171

ONCACBCG1CG2CONCACBCGCDCENZCONCACONCACBCGCDNECZNH1NH2CONCACBCGCD1CD2CE1CE2CZCONCA

SER HVAL HVAL HVAL HVAL HVAL HVAL HVAL HLYS HLYS HLYS HLYS HLYS HLYS HLYS HLYS HLYS HGLY HGLY HGLY HGLY HARG HARG HARG HARG HARG HARG HARG HARG HARG HARG HARG HPHE HPHE HPHE HPHE HPHE HPHE HPHE HPHE HPHE HPHE HPHE HTHR HTHR H

626363636363636364646464646464646465656565666666666666666666666667676767676767676767676868

32.46832.90031.69931.89032.65232.54131.04329.94631.67431.03731.87331.45332.29931.94232.87629.64829.43128.72927.36526.53325.34727.10826.28026.72926.99027.22928.57028.93128.03730.20026.38925.50327.48227.67229.02929.13728.31530.13728.49830.28329.51027.63627.96727.18527.043

50.52048.59748.38648.55049.66347.34246.94646.67846.04044.76743.82642.28341.55440.09239.34444.85545.58644.10544.16645.28845.34046.26947.24748.64748.90350.36950.74251.81352.56552.12447.08147.44146.54546.50147.04648.56949.39749.15650.73150.50351.31545.08344.18744.86343.466

17.41416.55215.84714.28514.05613.66216.07515.56716.78017.00717.90817.74118.81719.15320.20317.72218.78017.12817.60017.14717.46216.46315.78016.11217.66017.89117.59416.82316.27916.51914.29713.63513.75712.32211.86311.79412.53511.05912.49311.01211.68711.91512.70310.71610.208

55.3456.4156.6555.7654.3053.7157.6657.5758.6060.1961.4862.9364.3665.7365.4560.5962.2859.7258.6358.6259.1057.0755.7755.3153.2151.5849.3750.2648.6149.6455.5455.8054.9254.6255.5556.1854.8855.3556.5555.2755.2554.0953.4753.4754.52

HHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH

ONCCCCCONCCCCCNCONCCONCCCCNCNNCONCCCCCCCCCONC

517251735174517551765177517851795180518151825183518451855186518751885189519051915192519351945195519651975198519952005201520252035204520552065207520852095210521152125213521452155216

CBOG1CG2CONCACBCG2CG1CD1CONCACBOGCONCACBCGCDNECZNH1NH2CONCACBCGOD1OD2CONCACBCGOD1ND2C

THR HTHR HTHR HTHR HTHR HILE HILE HILE HILE HILE HILE HILE HILE HSER HSER HSER HSER HSER HSER HARG HARG HARG HARG HARG HARG HARG HARG HARG HARG HARG HASP HASP HASP HASP HASP HASP HASP HASP HASN HASN HASN HASN HASN HASN HASN H

686868686869696969696969697070707070707171717171717171717171727272727272727273737373737373

25.62325.22725.62627.36926.82528.41828.87130.53031.06231.03532.61328.28028.20427.86327.40125.90925.36627.70728.04527.52827.82129.16329.28030.57431.33132.63533.44333.13726.79426.26926.63625.75024.70623.58123.88122.46626.49126.75626.71127.57628.26429.16329.67429.24527.010

42.86342.72641.32443.49344.26842.75842.51542.47641.28342.60642.80141.29140.32341.28840.07240.01141.37640.19341.27439.13539.22038.50037.00036.46536.66136.75936.64536.86138.43537.44238.75238.08739.14438.60537.68539.18437.58338.36036.26735.77334.50134.66435.74333.63935.722

10.37211.7449.8478.6818.0088.3126.9036.8547.4795.3585.1956.3057.0255.0934.3934.4594.0722.8952.4442.1330.6850.3690.9460.945-0.344-0.5140.485-1.7210.0080.575-1.253-2.065-2.484-3.544-4.373-3.613-3.244-4.270-3.230-4.308-3.899-2.695-2.461-1.842-5.731

55.5056.1854.7454.0354.0052.8151.4851.2850.2449.6749.9651.2652.0950.5651.4150.5351.9051.6951.3951.7851.9250.8348.5747.0343.9144.4044.2542.9952.4052.0053.2254.3057.7261.2661.1263.5453.9654.6853.3553.4252.9654.6356.1153.9752.70

HHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH

COCCONCCCCCCONCCOCONCCCCNCNNCONCCCOOCONCCCONC

521752185219522052215222522352245225522652275228522952305231523252335234523552365237523852395240524152425243524452455246524752485249525052515252525352545255525652575258525952605261

ONCACBCONCACBCGCDNECZNH1NH2CONCACBCGOD1ND2CONCACBCG2CG1CD1CONCACBCGCD1CD2CONCACBCG

ASN HALA HALA HALA HALA HALA HARG HARG HARG HARG HARG HARG HARG HARG HARG HARG HARG HASN HASN HASN HASN HASN HASN HASN HASN HILE HILE HILE HILE HILE HILE HILE HILE HLEU HLEU HLEU HLEU HLEU HLEU HLEU HLEU HTYR HTYR HTYR HTYR H

737474747474757575757575757575757576767676767676767777777777777777787878787878787879797979

27.70125.70924.96323.44925.04825.13724.94625.02823.86122.48621.36120.69919.49918.64619.14726.35526.49127.36128.63229.31529.73130.39229.56328.44429.08627.72927.57926.12626.04025.72124.17327.99827.82528.61029.05930.56331.08831.18732.36528.29927.82628.03527.17725.74224.871

35.34435.80135.60135.16436.94037.02337.96039.26640.02439.95640.79839.88539.42639.71238.61140.07041.23439.47640.12140.25438.95838.82037.98241.54442.49441.55342.65343.10244.41143.63843.84242.38641.27043.38943.29443.64943.59642.15844.37144.31945.31544.03344.85544.14043.972

-6.643-5.830-7.134-6.989-7.773-8.944-6.946-7.416-6.712-7.445-6.811-5.884-5.935-6.877-5.004-7.320-7.849-6.669-6.510-7.918-8.434-9.470-7.603-5.865-6.227-4.754-3.929-3.973-3.140-5.331-5.549-2.487-1.957-1.863-0.509-0.4950.9291.5191.2070.352-0.0521.5532.3172.4981.172

52.4353.0753.7652.8253.9854.9153.4853.8456.7057.9060.3864.8865.9867.5368.4853.0151.3451.7250.7950.8851.7050.6452.1249.2247.5647.6947.9347.8048.1446.3745.8848.5448.8147.8448.5748.7347.6747.0447.5749.2150.4550.7552.0653.3555.87

HHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH

ONCCCONCCCCNCNNCONCCCONCONCCCCCCONCCCCCCONCCC

526252635264526552665267526852695270527152725273527452755276527752785279528052815282528352845285528652875288528952905291529252935294529552965297529852995300530153025303530453055306

CD1CE1CD2CE2CZOHCONCACBCGCD1CD2CONCACBCGCDOE1NE2CONCACBCGSDCECONCACBOGCONCACBOGCO

TYR HTYR HTYR HTYR HTYR HTYR HTYR HTYR HLEU HLEU HLEU HLEU HLEU HLEU HLEU HLEU HGLN HGLN HGLN HGLN HGLN HGLN HGLN HGLN HGLN HMET HMET HMET HMET HMET HMET HMET HMET HSER HSER HSER HSER HSER HSER HSER HSER HSER HSER HSER HSER H

7979797979797979808080808080808081818181818181818182A82A82A82A82A82A82A82A82B82B82B82B82B82B82C82C82C82C82C82C

24.57823.73524.37423.57223.24722.60927.70228.36527.28927.60828.80229.22229.69930.22626.40525.92325.77224.60423.56822.38321.42320.97221.38725.05525.68324.64125.02125.70726.92427.89827.09123.82622.82924.01122.88022.14022.90223.44924.66922.63523.17423.47522.61924.37725.334

42.71042.55645.04344.88243.65043.53345.19144.35846.36046.71847.56348.07846.92549.25447.40248.43146.70347.21546.12546.53347.26446.66448.60847.76346.97548.99549.78451.07950.87752.39052.77550.25450.79550.19950.39349.04848.28751.10851.13851.84652.80852.03250.93153.60853.623

0.663-0.4810.491-0.639-1.054-2.2523.6334.2664.1525.5215.4936.9057.7137.0786.1805.6657.1127.8368.2219.1278.2517.2788.3759.1109.9599.33110.48410.0039.0248.7557.37611.26410.70212.55613.47713.72714.71414.76114.98015.45916.49817.78417.72016.15416.938

56.5157.9855.7256.3158.4560.1252.1551.2552.1852.7251.0552.4453.2051.8053.6353.0054.5255.6956.6258.3360.6762.4960.5556.8257.6158.2860.2661.1662.8964.3862.4560.4260.1360.0760.4959.1061.6160.6761.3960.0761.0761.2960.8761.6561.63

HHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH

CCCCCOCONCCCCCCONCCCCONCONCCCSCCONCCOCONCCOCO

530753085309531053115312531353145315531653175318531953205321532253235324532553265327532853295330533153325333533453355336533753385339534053415342534353445345534653475348534953505351

NCACBCGCD1CD2CONCACBCGCDNECZNH1NH2CONCACBOGCONCACBCGCDOE1OE2CONCACBCGOD1OD2CONCACB

LEU HLEU HLEU HLEU HLEU HLEU HLEU HLEU HARG HARG HARG HARG HARG HARG HARG HARG HARG HARG HARG HSER HSER HSER HSER HSER HSER HGLU HGLU HGLU HGLU HGLU HGLU HGLU HGLU HGLU HASP HASP HASP HASP HASP HASP HASP HASP HTHR HTHR HTHR H

82D82D82D82D82D82D82D82D83838383838383838383838484848484848585858585858585858686868686868686878787

24.35325.43324.97924.97524.38626.46125.68524.71826.92827.28628.03528.08928.59228.36229.25130.40828.94428.07728.56428.29629.00729.12929.59830.36730.79631.00832.35632.81832.60231.40331.38730.60232.38533.41231.25331.15829.88030.01729.03031.05031.24331.33931.28631.32531.069

54.23555.10255.73954.68755.07954.22556.27356.90156.52157.66957.27555.69355.26353.88352.93453.14551.72658.59758.16959.83760.90662.22061.96360.43460.79059.64259.03758.09858.83358.37857.22459.22658.09257.53957.77456.81455.99154.95154.96354.21057.47556.83658.78359.66961.194

14.97114.50813.15612.06910.89711.71815.48915.98815.85016.67117.95318.18219.51619.94219.92419.35620.40715.79514.72016.31015.51116.24917.50015.05913.90815.94415.63516.79817.95918.75219.12519.06114.49414.30713.90812.86413.03614.08414.83414.37511.48910.41311.57910.41710.922

61.4161.7260.3759.2457.4358.3962.7164.1063.6664.3564.3067.3369.2072.2373.3473.9974.4564.0063.7663.4062.9062.7664.9562.1762.0560.4859.6759.8363.3364.3665.1566.2858.3959.0256.0854.1155.3357.0558.3655.5852.3450.0149.5948.6348.91

HHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH

NCCCCCCONCCCCNCNNCONCCOCONCCCCOOCONCCCOOCONCC

535253535354535553565357535853595360536153625363536453655366536753685369537053715372537353745375537653775378537953805381538253835384538553865387538853895390539153925393539453955396

OG1CG2CONCACBCONCACBCGSDCECONCACBCGCD1CE1CD2CE2CZOHCONCACBCGCD1CE1CD2CE2CZOHCONCACO

THR HTHR HTHR HTHR HALA HALA HALA HALA HALA HMET HMET HMET HMET HMET HMET HMET HMET HTYR HTYR HTYR HTYR HTYR HTYR HTYR HTYR HTYR HTYR HTYR HTYR HTYR HTYR HTYR HTYR HTYR HTYR HTYR HTYR HTYR HTYR HTYR HTYR HCYS HCYS HCYS HCYS H

878787878888888888898989898989898990909090909090909090909091919191919191919191919192929292

29.73731.25032.61433.65132.52533.69634.21933.42332.26034.49834.48835.70435.66234.19734.71634.66635.59133.62633.57632.15331.82232.06931.77831.54331.37631.50231.43034.06133.50135.16035.63837.21437.76138.37438.70837.78938.18538.80739.16835.35635.51635.12835.00536.38036.965

61.38262.30659.47159.59859.24358.81657.70558.56558.44258.43357.82758.34757.80658.35159.89456.30555.85855.52854.05953.64853.77452.77052.89054.97055.17554.12554.15753.43553.70852.73352.12752.31553.72954.49055.82054.26755.41556.20357.45550.63449.86050.12748.67048.31948.974

11.5229.9039.75110.3638.4447.6568.1776.2665.8725.4744.1733.4191.9220.9160.3714.3314.8964.0074.0514.3745.8996.7718.1056.4467.8238.65310.0182.6631.5962.6661.4361.3561.2022.2592.057-0.090-0.3120.6660.2141.4382.4070.2370.074-0.337-1.220

50.3048.8447.7145.9345.9844.6643.8544.6845.7944.0843.1143.9045.3550.5445.9744.2744.1843.9743.9342.7442.4942.7141.9941.2841.0441.5441.1144.5644.7742.9643.9142.4143.9441.9144.3942.9145.6046.1150.4544.7043.0945.6946.1044.5243.72

HHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH

OCCONCCCONCCCSCCONCCCCCCCCOCONCCCCCCCCOCONCCO

539753985399540054015402540354045405540654075408540954105411541254135414541554165417541854195420542154225423542454255426542754285429543054315432543354345435543654375438543954405441

CBSGNCACBCONCACBCGCDNECZNH1NH2CONCACBCGCD1CD2CONCACBCGOD1OD2CONCACONCACBCGCD1CE1CD2

CYS HCYS HALA HALA HALA HALA HALA HARG HARG HARG HARG HARG HARG HARG HARG HARG HARG HARG HLEU HLEU HLEU HLEU HLEU HLEU HLEU HLEU HASP HASP HASP HASP HASP HASP HASP HASP HGLY HGLY HGLY HGLY HTYR HTYR HTYR HTYR HTYR HTYR HTYR H

929293939393939494949494949494949494959595959595959596969696969696969797979798989898989898

34.03133.78436.77338.07939.25638.02237.48538.86239.05339.57639.50139.92941.33741.99141.35743.27640.20141.24039.93240.99740.28941.12142.37440.12041.58440.90342.76543.55744.54143.88842.72944.52644.21244.55144.14544.66245.75146.43345.86746.92146.87547.03248.21648.41846.007

48.49846.88547.12646.58146.93545.11744.40944.62843.21442.86241.39840.95440.99740.67240.53140.56542.74643.21541.77641.44541.19140.42041.23740.34740.26339.28140.36739.27339.67640.05140.53540.12538.42737.31538.74837.90538.57739.51038.10438.59638.00636.53035.95334.64635.760

-1.175-1.690-0.042-0.6080.540-0.6270.487-1.461-1.645-3.109-3.350-4.994-5.159-6.278-7.402-6.311-0.761-0.8170.0811.1892.4703.5413.7394.7280.8040.7400.208-0.364-1.408-2.741-2.757-3.8400.6000.1971.9332.9353.8893.4875.1405.9407.3367.3857.8057.7397.288

47.3856.0643.3543.4941.9443.7845.3443.4544.2645.2446.4447.2849.7050.4050.4646.1044.8145.0244.5543.7441.4942.0943.9743.5744.1346.0344.8945.3044.9248.1648.5649.2546.3348.0046.2845.8046.6345.5845.5045.6744.7245.0145.5746.4543.79

HHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH

CSNCCCONCCCCNCNNCONCCCCCCONCCCOOCONCCONCCCCCC

544254435444544554465447544854495450545154525453545454555456545754585459546054615462546354645465546654675468546954705471547254735474547554765477547854795480548154825483548454855486

CE2CZOHCONCACBCGCD1CE1CD2CE2CZOHCONCACBCGCD1CD2CE1CE2CZCONCACONCACBCGCD1CD2CE1CE2CZCONCA

TYR HTYR HTYR HTYR HTYR HTYR HTYR HTYR HTYR HTYR HTYR HTYR HTYR HTYR HTYR HTYR HTYR HPHE HPHE HPHE HPHE HPHE HPHE HPHE HPHE HPHE HPHE HPHE HGLY HGLY HGLY HGLY HPHE HPHE HPHE HPHE HPHE HPHE HPHE HPHE HPHE HPHE HPHE HALA HALA H

9898989898999999999999999999999999100A100A100A100A100A100A100A100A100A100A100A100B100B100B100B100C100C100C100C100C100C100C100C100C100C100C101101

46.08947.31947.43948.29849.09648.58749.81250.22750.75251.86852.25449.98250.42251.53251.95549.82950.88048.73548.71547.95048.52048.08749.65048.68750.14449.75648.16348.32247.42946.91845.53044.85545.08743.87643.43742.85243.53441.80642.98841.25641.77544.31044.85644.11244.715

34.33633.80932.51538.57639.33437.71437.62436.08235.17635.54834.85534.05033.28633.71632.91038.48338.71538.96239.84439.13637.79036.76437.66835.46336.42035.28841.26942.03741.62743.01343.25942.36044.49144.96946.20746.00346.46145.15346.28644.86045.40145.38646.55844.50844.704

7.4737.7017.9455.3505.8174.3243.6303.1534.2855.0076.0734.8015.7876.5017.4102.3601.7721.8750.745-0.406-0.721-0.162-1.444-0.394-1.925-1.1870.851-0.0711.8832.0461.3660.9121.3650.7451.4552.6973.9772.8625.0544.4625.277-0.689-0.957-1.626-2.982

45.1445.9747.0245.3146.7144.7843.3145.3347.9349.0650.8348.7250.5651.0850.5941.5742.2441.1941.3941.1440.3139.7239.5940.5841.2241.7541.0940.9741.6040.6741.0640.7539.3039.1036.6337.3437.4937.2737.4337.9838.0538.9237.9938.3738.04

HHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH

CCOCONCCCCCCCCOCONCCCCCCCCCONCCONCCCCCCCCCONC

548754885489549054915492549354945495549654975498549955005501550255035504550555065507550855095510551155125513551455155516551755185519552055215522552355245525552655275528552955305531

CBCONCACBCGCD1CE1CD2CE2CZOHCONCACBCGCD2CE2CE3CD1NE1CZ2CZ3CH2CONCACONCACBCGCDOE1NE2CONCAC

ALA HALA HALA HTYR HTYR HTYR HTYR HTYR HTYR HTYR HTYR HTYR HTYR HTYR HTYR HTRP HTRP HTRP HTRP HTRP HTRP HTRP HTRP HTRP HTRP HTRP HTRP HTRP HTRP HGLY HGLY HGLY HGLY HGLN HGLN HGLN HGLN HGLN HGLN HGLN HGLN HGLN HGLY HGLY HGLY H

101101101102102102102102102102102102102102102103103103103103103103103103103103103103103104104104104105105105105105105105105105106106106

44.74143.88844.45942.62441.82340.88141.77042.48743.46342.17643.13943.69744.66540.80740.25940.62539.71740.38641.47141.59542.75240.79142.66743.38543.17941.25742.42938.80539.06837.60336.64936.86237.83935.89936.00135.21536.01237.57737.89138.50635.54135.88134.82734.52633.100

43.31045.61746.12545.84946.75645.94045.48544.25543.80746.39945.95344.63544.23647.55146.92548.83849.64550.61850.17450.50349.88551.20349.43949.24750.04951.32150.77750.44050.68750.64651.49452.96953.34253.81255.26355.92755.51456.07857.32455.15155.82656.98055.04755.50056.020

-3.802-3.860-4.821-3.587-4.421-5.415-6.594-6.486-7.469-7.510-8.505-8.507-9.426-3.509-2.531-3.783-3.097-2.117-1.2490.1740.6611.095-1.605-0.4232.0002.4472.818-3.949-5.092-3.465-4.232-3.990-3.435-4.380-4.372-5.448-6.818-7.031-6.794-7.495-3.186-2.926-2.408-1.099-1.125

37.2638.7039.2237.8840.7343.7146.3946.6147.4046.3148.9550.4250.8941.6741.2141.7744.3942.1642.5941.4340.6138.6341.5441.9437.9637.6937.3645.6245.7646.0349.3450.3950.0451.4753.7758.0863.9167.4070.5168.6153.7752.0053.7653.0953.25

HHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH

CCONCCCCCCCCOCONCCCCCCCNCCCCONCCONCCCCONCONCC

553255335534553555365537553855395540554155425543554455455546554755485549555055515552555355545555555655575558555955605561556255635564556555665567556855695570557155725573557455755576

ONCACBOG1CG2CONCACBCGCD1CD2CONCACBCG1CG2CONCACBCONCACBCG1CG2CONCACBOGCONCACBC

GLY HTHR HTHR HTHR HTHR HTHR HTHR HTHR HLEU HLEU HLEU HLEU HLEU HLEU HLEU HLEU HVAL HVAL HVAL HVAL HVAL HVAL HVAL HALA HALA HALA HALA HALA HVAL HVAL HVAL HVAL HVAL HVAL HVAL HSER HSER HSER HSER HSER HSER HALA HALA HALA HALA H

106107107107107107107107108108108108108108108108109109109109109109109110110110110110111111111111111111111112112112112112112113113113113

32.66232.32031.06829.82228.56329.56331.01031.35630.61830.54630.71132.06432.02933.00929.32928.27229.53228.47128.52827.55828.36028.58629.61127.58227.54727.44926.46025.36826.89326.07526.75625.74827.15525.94626.83824.80024.56425.07624.80523.06122.26922.63421.21920.75320.861

56.52955.87856.57055.62556.38454.70357.20256.58858.47159.23760.73461.42062.93961.32659.03059.08558.95558.80857.42157.36156.21359.88259.94860.77061.70163.10261.44161.18561.33861.03660.13859.63458.79562.35862.79763.01264.42065.40966.84764.59664.09665.32665.76665.88267.043

-2.182-0.0550.001-0.204-0.2420.9941.2972.3031.3462.6192.3832.1621.7773.4143.4832.9984.7865.6956.3607.4735.3606.8567.5547.0198.1207.6269.1108.71210.33611.45512.38113.56511.64612.13812.77311.98712.42411.26911.47312.67511.87113.72413.78715.17912.965

53.5851.3749.5849.8652.0148.3249.7649.7450.5351.5252.3956.7054.6256.2250.3748.7849.4250.4050.3549.6449.0951.5651.1651.3852.8052.4152.9852.4754.0055.5555.0955.1853.8657.6157.5059.5862.0662.2763.4464.0164.8765.8967.7767.0069.23

HHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH

ONCCOCCONCCCCCCONCCCCCONCCCONCCCCCONCCOCONCCC

557755785579558055815582558355845585558655875588558955905591559255935594559555965597559855995600560156025603560456055606560756085609561056115612561356145615561656175618561956205621

ONCACBCONCACBCGCDCENZCONCACBOG1CG2CONCACBOG1CG2CONCDCACBCGCONCDCACBCGCONCA

ALA HALA HALA HALA HALA HALA HLYS HLYS HLYS HLYS HLYS HLYS HLYS HLYS HLYS HTHR HTHR HTHR HTHR HTHR HTHR HTHR HTHR HTHR HTHR HTHR HTHR HTHR HTHR HPRO HPRO HPRO HPRO HPRO HPRO HPRO HPRO HPRO HPRO HPRO HPRO HPRO HPRO HSER HSER H

113114114114114114115115115115115115115115115116116116116116116116117117117117117117117118118118118118118118119119119119119119119120120

19.72921.83621.55622.83220.86420.69820.52319.58818.33217.02915.72214.47913.41720.23720.97319.76120.33020.18819.39819.52020.04519.01521.02820.73721.32121.00920.67721.30722.44620.55819.10921.17219.97318.90722.08922.10023.02023.31823.98225.14024.41923.37922.56423.73523.541

67.36967.67468.74569.47268.28367.06169.29369.07569.99669.22070.07669.94170.96869.34470.40068.56568.73167.57567.96266.45870.09570.59570.73672.00973.13572.94974.46972.13371.90472.46472.72972.61372.67673.31473.82074.70273.75972.60774.86574.22973.20775.89475.53377.13778.148

12.72812.36811.38311.04210.1319.8679.3078.2258.3988.8658.4459.4149.0506.9016.7125.9254.6593.7002.5804.3324.1384.3713.5242.8793.7185.1533.1611.5161.3790.4970.435-0.815-1.794-1.007-0.850-0.001-1.772-2.675-1.927-2.653-3.526-2.789-3.519-2.578-3.511

69.6569.9971.2070.3772.6872.4373.4774.9776.2978.9080.8482.5484.3874.5774.1574.0574.8475.8178.7277.1874.3574.8973.1972.5272.5072.6571.3271.6272.2470.5470.3069.8170.0369.3669.3068.9369.6369.2469.4369.5969.9669.5469.3569.0569.34

HHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH

ONCCCONCCCCCNCONCCOCCONCCOCCONCCCCCONCCCCCONC

562256235624562556265627562856295630563156325633563456355636563756385639564056415642564356445645564656475648564956505651565256535654565556565657565856595660566156625663566456655666

CBOGCONCACBCG1CG2CONCACBCGCD1CE1CD2CE2CZOHCONCDCACBCGCONCACBCGCD1CD2CONCACBCONCD

SER HSER HSER HSER HVAL HVAL HVAL HVAL HVAL HVAL HVAL HTYR HTYR HTYR HTYR HTYR HTYR HTYR HTYR HTYR HTYR HTYR HTYR HPRO HPRO HPRO HPRO HPRO HPRO HPRO HLEU HLEU HLEU HLEU HLEU HLEU HLEU HLEU HALA HALA HALA HALA HALA HPRO HPRO H

120120120120121121121121121121121122122122122122122122122122122122122123123123123123123123124124124124124124124124125125125125125126126

23.38822.28024.79025.82524.68325.78225.58126.66025.50425.90325.00627.03527.09727.32626.31825.01824.03626.65925.69124.35823.28928.27829.30328.14226.99929.22528.49527.29730.22829.83931.50032.46433.51533.04534.23032.58533.14733.89433.00533.44232.25234.25833.97735.29835.713

79.43879.35178.22278.20078.40678.42977.26977.22775.93379.75980.21380.35181.68382.74182.78782.94182.96882.58582.63182.84982.92981.72481.21182.40183.25382.37382.61883.64483.45584.54283.20984.21583.68683.17382.37284.32084.64183.89785.91586.47386.76587.70588.37587.96787.225

-2.776-1.990-4.362-3.817-5.682-6.568-7.538-8.681-6.683-7.337-7.833-7.514-8.072-7.030-5.901-6.191-5.212-4.584-3.591-3.962-3.129-9.056-8.764-10.181-10.618-11.168-12.519-12.077-10.829-10.394-11.057-10.808-9.820-8.499-7.902-7.676-12.061-12.645-12.348-13.631-14.462-13.366-12.373-14.181-15.370

69.0669.8369.6570.9969.0768.4967.9966.5067.1968.5969.4468.0468.4966.9165.9465.7264.5564.7964.0563.9363.0369.8469.1171.6071.6173.0072.2071.5374.2875.0375.5777.1876.3375.6375.4875.2278.6478.8180.8982.4981.4983.3883.4984.6284.56

HHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH

COCONCCCCCONCCCCCCCCOCONCCCCCONCCCCCCONCCCONC

566756685669567056715672567356745675567656775678567956805681568256835684568556865687568856895690569156925693569456955696569756985699570057015702570357045705570657075708570957105711

CACBCGCONCACBCONCACBCONCACBCGSDCECONCACBCG1CG2CONCACBOG1CG2CONCACBCGCD1CD2CO

PRO HPRO HPRO HPRO HPRO HALA HALA HALA HALA HALA HALA HALA HALA HALA HALA HMET HMET HMET HMET HMET HMET HMET HMET HVAL HVAL HVAL HVAL HVAL HVAL HVAL HTHR HTHR HTHR HTHR HTHR HTHR HTHR HLEU HLEU HLEU HLEU HLEU HLEU HLEU HLEU H

126126126126126133133133133133134134134134134135135135135135135135135136136136136136136136137137137137137137137138138138138138138138138

36.21637.08336.29635.53434.53745.01546.01447.39945.85044.76646.97946.94148.33745.92045.21545.88744.97445.80746.71845.79044.93443.97744.17242.85441.83840.79339.80240.04141.16440.85740.97440.30641.22240.56042.51938.95738.77338.05636.71735.78436.14935.42235.78736.56637.440

89.09589.03088.30890.46590.90388.62088.47388.53987.15086.59486.66985.42384.80184.43983.73684.37683.44482.45981.59580.60179.55384.16785.30183.47784.06584.74283.70385.79383.00981.90383.37182.45482.22782.67583.02383.01184.21182.02582.19681.76882.43181.81083.91781.21780.402

-13.959-15.205-16.113-13.871-14.349-19.518-20.570-19.927-21.322-21.442-21.875-22.633-22.599-22.055-22.766-20.712-20.061-19.241-20.115-21.291-20.106-19.152-18.736-18.881-18.018-18.905-19.426-18.110-17.140-17.565-15.858-14.943-13.740-12.555-13.911-14.480-14.320-14.373-13.866-14.997-16.321-17.526-16.316-12.706-12.420

85.6685.3184.8586.6186.8987.9088.8688.4489.2889.7089.6990.0090.2690.1990.0589.6588.4089.0589.9792.1890.4987.0287.1285.5083.7683.9883.3383.6682.1882.4780.4179.7679.3279.4578.6178.4978.2977.7377.4778.1079.5079.3578.8276.7376.08

HHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH

CCCCONCCCONCCCONCCCSCCONCCCCCONCCOCCONCCCCCCO

571257135714571557165717571857195720572157225723572457255726572757285729573057315732573357345735573657375738573957405741574257435744574557465747574857495750575157525753575457555756

NCACONCACOCBSGNCACBCGCD1CD2CONCACBCG1CG2CONCACBCGCDCENZCONCACONCACBCGCD1CE1CD2

GLY HGLY HGLY HGLY HCYS HCYS HCYS HCYS HCYS HCYS HLEU HLEU HLEU HLEU HLEU HLEU HLEU HLEU HVAL HVAL HVAL HVAL HVAL HVAL HVAL HLYS HLYS HLYS HLYS HLYS HLYS HLYS HLYS HLYS HGLY HGLY HGLY HGLY HTYR HTYR HTYR HTYR HTYR HTYR HTYR H

139139139139140140140140140140141141141141141141141141142142142142142142142143143143143143143143143143144144144144145145145145145145145

35.42835.18533.69932.80733.46032.11532.11832.97931.76830.53131.16631.13331.07130.91032.10030.76629.93828.81330.25229.21429.61728.54429.79729.06329.93127.89527.72827.56827.80027.45227.47628.80526.50225.39026.80925.78525.11423.92525.91425.31025.75427.21127.70229.02128.071

81.31880.38580.19680.74079.32379.01878.99078.40077.60877.71679.67579.58081.02281.24580.82682.72978.72278.81677.76676.86375.45274.44075.40077.01276.68377.60478.23979.74080.53682.00482.69082.54377.73777.67177.29777.10275.71875.57574.67073.33272.73272.41971.22570.86273.235

-11.999-10.926-10.655-11.324-9.639-9.174-7.664-7.062-9.693-10.993-7.033-5.599-5.092-3.583-2.720-3.303-5.186-5.720-4.287-3.806-4.218-3.846-5.719-2.312-1.511-1.972-0.671-0.9120.3680.2371.5972.2220.069-0.4391.3022.3182.2732.4851.9691.8140.4700.4690.9730.786-0.241

76.1976.0975.9475.8976.3576.8075.3475.5278.1983.3073.4770.9870.2169.2768.1368.7869.2369.9066.6864.2564.2461.9461.9863.4662.7362.4461.5561.6364.1866.9567.2069.9860.0859.8158.6558.0157.9857.3557.9057.3357.6159.8459.6261.6960.20

HHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH

NCCONCCOCSNCCCCCCONCCCCCONCCCCCNCONCCONCCCCCC

575757585759576057615762576357645765576657675768576957705771577257735774577557765777577857795780578157825783578457855786578757885789579057915792579357945795579657975798579958005801

CE2CZOHCONCACBCGCD1CD2CE1CE2CZCONCDCACBCGCONCACBCGCDOE1OE2CONCDCACBCGCONCACBCG1CG2C

TYR HTYR HTYR HTYR HTYR HPHE HPHE HPHE HPHE HPHE HPHE HPHE HPHE HPHE HPHE HPHE HPRO HPRO HPRO HPRO HPRO HPRO HPRO HGLU HGLU HGLU HGLU HGLU HGLU HGLU HGLU HGLU HPRO HPRO HPRO HPRO HPRO HPRO HPRO HVAL HVAL HVAL HVAL HVAL HVAL H

145145145145145146146146146146146146146146146146147147147147147147147148148148148148148148148148149149149149149149149150150150150150150

29.40829.88731.23325.70726.69124.90725.26924.97725.23926.49724.22826.75324.49225.75324.39523.22524.94824.29926.34726.33725.31627.19526.74928.48129.36030.81831.48332.92233.83833.11728.86628.27129.15628.96529.91230.90930.05729.12127.93029.84429.32429.14628.01630.44930.290

72.87971.69971.37172.39172.59571.33870.30770.86369.83169.74468.95368.78167.99167.88969.07969.17767.83766.56367.58066.15565.39867.56467.89167.17966.82966.67367.96368.09267.84368.61465.46864.68665.24163.97366.11865.16763.94466.78166.56367.65468.07969.60870.10570.32667.734

-0.4280.108-0.0082.9743.6623.2164.2095.6186.6867.2677.0798.2338.0478.6143.9363.6004.0333.7604.3994.9584.1543.1302.0313.3302.2272.7553.2682.7353.4781.6411.6722.3840.375-0.326-0.486-1.114-1.504-1.643-1.847-2.427-3.723-3.809-2.912-3.507-4.807

60.8561.5163.3657.1656.8657.2357.0357.4057.3856.7957.3156.8457.7356.9457.7858.2757.9157.2256.5157.1357.2756.5655.4555.9955.9155.8257.4960.4162.5960.2154.7755.3954.0652.9754.9454.5754.4256.2957.6357.0856.7256.1155.6956.1457.76

HHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH

CCOCONCCCCCCCCCONCCCCCONCCCCOOCONCCCCCONCCCCC

580258035804580558065807580858095810581158125813581458155816581758185819582058215822582358245825582658275828582958305831583258335834583558365837583858395840584158425843584458455846

ONCACBOG1CG2CONCACBCG1CG2CONCACBOG1CG2CONCACBCGCD2CE2CE3CD1NE1CZ2CZ3CH2CONCACBCGOD1ND2CON

VAL HTHR HTHR HTHR HTHR HTHR HTHR HTHR HVAL HVAL HVAL HVAL HVAL HVAL HVAL HTHR HTHR HTHR HTHR HTHR HTHR HTHR HTRP HTRP HTRP HTRP HTRP HTRP HTRP HTRP HTRP HTRP HTRP HTRP HTRP HTRP HASN HASN HASN HASN HASN HASN HASN HASN HSER H

150151151151151151151151152152152152152152152153153153153153153153154154154154154154154154154154154154154154155155155155155155155155156

31.43029.83730.71530.35331.47629.13230.62829.55631.82331.90332.73733.05032.02032.62633.66732.01032.73932.10930.72032.26032.63931.84533.50633.34734.61934.74834.19134.61833.42535.49335.44734.23333.05533.45333.10733.63832.26031.58532.34432.37131.39933.58431.21631.40630.667

67.33867.93867.62966.21165.61366.23368.69569.17169.13070.22771.30472.43171.83969.78969.15870.06969.92768.78769.05067.44871.21172.10771.32072.39573.25073.98075.29975.65076.18273.61674.55676.88777.40777.75771.79970.75072.52472.00772.40573.90374.61474.39370.50269.81870.010

-4.587-6.018-7.095-7.573-8.226-8.489-8.174-8.551-8.609-9.539-8.867-9.854-7.646-10.789-10.717-11.955-13.195-14.003-14.214-13.266-13.991-13.682-15.015-15.980-15.939-14.636-14.369-13.034-15.096-13.492-12.501-12.518-14.581-13.283-17.383-17.717-18.176-19.404-20.678-20.835-20.572-21.194-19.442-20.459-18.306

57.8959.1660.2861.1362.6561.4060.4261.4360.6360.8061.1859.5560.6361.8561.6163.1364.5564.4666.1563.2165.3565.8267.7370.4771.1871.9672.2772.9372.3472.8172.5573.0073.0173.6071.9672.4973.4174.7873.6772.8572.1573.1776.0376.9077.24

HHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH

ONCCOCCONCCCCCONCCOCCONCCCCCCCNCCCCONCCCONCON

584758485849585058515852585358545855585658575858585958605861586258635864586558665867586858695870587158725873587458755876587758785879588058815882588358845885588658875888588958905891

CACBOGCONCACONCACBCONCACBCGCD1CD2CONCACBOGCONCACBOGCONCACONCACBCG1CG2CO

SER HSER HSER HSER HSER HGLY HGLY HGLY HGLY HALA HALA HALA HALA HALA HLEU HLEU HLEU HLEU HLEU HLEU HLEU HLEU HSER HSER HSER HSER HSER HSER HSER HSER HSER HSER HSER HSER HGLY HGLY HGLY HGLY HVAL HVAL HVAL HVAL HVAL HVAL HVAL H

156156156156156157157157157158158158158158159159159159159159159159160160160160160160161161161161161161162162162162163163163163163163163

30.03628.85727.89731.01630.66832.28833.35434.48735.64234.09835.03034.29736.30637.40736.12037.25536.71837.22436.51438.71637.78637.15039.00239.49139.45839.47740.91141.48641.51542.79743.86444.21242.74341.89043.72043.70842.53542.09842.00540.92639.90639.10138.94541.42742.045

68.67468.60069.58667.49166.34367.82866.84867.34966.95168.24668.60669.43369.29268.84870.40271.13472.52473.54074.88573.82270.53670.57069.96969.28367.78367.58069.69969.24970.53071.12770.72169.35672.65373.36973.11274.46774.68575.80373.51173.47072.37571.96272.86673.17072.151

-18.239-19.221-18.822-18.355-18.630-18.097-18.140-19.033-18.923-19.969-21.029-22.089-20.525-20.789-19.776-19.228-18.926-19.951-19.863-19.816-17.917-16.885-17.978-16.784-17.075-18.489-16.408-15.415-17.297-16.948-17.960-17.737-16.771-17.292-15.955-15.436-14.455-14.213-13.941-12.941-13.308-12.064-14.357-11.526-11.247

78.9279.6280.2879.8180.4580.2280.3180.5080.7380.6681.0281.0581.0980.8281.4881.1281.4980.6880.5381.0281.1080.6781.3681.2081.8882.7180.7681.6979.3678.1978.4780.4476.7676.3675.5173.3971.7272.4368.9766.4166.1764.6465.3865.5465.66

HHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH

CCOCONCCONCCCONCCCCCCONCCOCONCCOCONCCONCCCCCO

589258935894589558965897589858995900590159025903590459055906590759085909591059115912591359145915591659175918591959205921592259235924592559265927592859295930593159325933593459355936

NCACBCGCD2ND1CE1NE2CONCACBOG1CG2CONCACBCGCD1CD2CE1CE2CZCONCDCACBCGCONCACBCONCACBCG1CG2

HIS HHIS HHIS HHIS HHIS HHIS HHIS HHIS HHIS HHIS HTHR HTHR HTHR HTHR HTHR HTHR HTHR HPHE HPHE HPHE HPHE HPHE HPHE HPHE HPHE HPHE HPHE HPHE HPRO HPRO HPRO HPRO HPRO HPRO HPRO HALA HALA HALA HALA HALA HVAL HVAL HVAL HVAL HVAL H

164164164164164164164164164164165165165165165165165166166166166166166166166166166166167167167167167167167168168168168168169169169169169

41.13841.38042.28943.71344.44444.54845.73345.70140.04539.41739.57138.43037.53136.95436.39438.92139.63138.57739.18839.25040.12439.59341.45740.41342.27441.75238.40137.21039.13340.55938.46339.56340.87437.40737.59336.24735.22333.99735.72436.55435.21635.31435.94737.46235.394

74.14373.98675.16875.00275.90073.99474.25975.39274.07075.11472.90072.87571.67971.95371.43572.72871.79773.74773.84475.33076.13676.61376.40877.31177.11077.55673.04372.82672.55272.60171.78871.37371.44072.65473.83972.01872.78371.88673.22972.58974.41274.88076.27476.14377.109

-10.634-9.217-8.825-9.366-10.192-8.998-9.619-10.339-8.445-8.357-7.924-6.986-7.383-8.661-6.374-5.529-5.164-4.680-3.346-2.943-3.886-5.092-3.551-5.980-4.445-5.660-2.279-2.376-1.254-0.985-0.1800.8120.0540.5110.7310.8501.5701.7702.9393.5763.3484.7204.7204.5653.577

64.2862.6862.7061.6761.6161.5961.7961.7362.2562.6560.5058.5758.5757.8756.8857.2557.2655.3253.4851.9350.8749.8750.5348.3650.7948.1652.8953.5152.2650.5952.2351.2851.1253.2253.1754.7756.8256.5958.4358.6061.2964.9865.1064.8466.13

HHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH

NCCCCNCNCONCCOCCONCCCCCCCCCONCCCCCONCCCONCCCC

593759385939594059415942594359445945594659475948594959505951595259535954595559565957595859595960596159625963596459655966596759685969597059715972597359745975597659775978597959805981

CONCACBCGCD1CD2CONCACBCGCDOE1OE2CONCACBOGCONCACBCGOD1OD2CONCACBCGCD1CD2CONCACBCG

VAL HVAL HLEU HLEU HLEU HLEU HLEU HLEU HLEU HLEU HGLU HGLU HGLU HGLU HGLU HGLU HGLU HGLU HGLU HSER HSER HSER HSER HSER HSER HASP HASP HASP HASP HASP HASP HASP HASP HLEU HLEU HLEU HLEU HLEU HLEU HLEU HLEU HTYR HTYR HTYR HTYR H

169169170170170170170170170170171171171171171171171171171172172172172172172173173173173173173173173174174174174174174174174175175175175

33.94532.89733.97532.72632.78631.53430.28431.66832.49733.21631.47331.14731.19330.36631.23130.70332.43629.76928.73229.78628.53827.82827.62627.62126.56428.09727.31527.84228.15828.79627.79926.81025.70527.65627.40226.48825.02524.08424.46928.71729.66028.78530.00130.16530.532

74.90775.04374.72574.63173.36773.15872.87871.97575.86176.12476.65077.82979.05480.22081.07681.97380.83677.70477.77577.46677.28078.63078.93076.25076.55674.98773.88072.49172.41173.33671.41474.05673.66774.69774.69675.87575.61276.74974.33674.77775.46074.00674.02072.64671.653

5.4034.7806.7347.4758.3409.1948.35610.1598.3599.3157.9858.7807.8648.4069.3049.9459.3539.4308.78410.75511.48711.60412.98510.81910.28310.83710.28010.62912.11412.61612.7388.8468.4878.0176.5796.2196.5946.1705.9585.8066.1874.7043.9063.2644.307

66.3466.6368.7771.6270.8170.0468.7369.0574.4274.9877.3980.4782.6685.4086.5687.0386.2881.6182.5582.4483.4384.8286.8083.3283.5782.6680.8784.2087.1588.1988.1078.0678.0173.9570.4170.0870.4370.0669.6767.7966.6264.8262.2362.2362.65

HHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH

CONCCCCCCONCCCCOOCONCCOCONCCCOOCONCCCCCCONCCC

598259835984598559865987598859895990599159925993599459955996599759985999600060016002600360046005600660076008600960106011601260136014601560166017601860196020602160226023602460256026

CD1CE1CD2CE2CZOHCONCACBOG1CG2CONCACBCGCD1CD2CONCACBOGCONCACBOGCONCACBOGCONCACBCG1

TYR HTYR HTYR HTYR HTYR HTYR HTYR HTYR HTHR HTHR HTHR HTHR HTHR HTHR HTHR HLEU HLEU HLEU HLEU HLEU HLEU HLEU HLEU HSER HSER HSER HSER HSER HSER HSER HSER HSER HSER HSER HSER HSER HSER HSER HSER HSER HSER HVAL HVAL HVAL HVAL H

175175175175175175175175176176176176176176176177177177177177177177177178178178178178178179179179179179179180180180180180180181181181181

31.85532.21729.56929.93531.25431.62029.94728.90431.14531.27131.33730.08031.66232.53533.60732.40633.64433.99733.20533.30833.71733.66232.70234.83934.91535.45536.83735.78736.60335.54036.33935.51836.31336.67535.88937.91638.39839.55540.78138.84039.22138.72039.19137.99237.011

71.54270.59770.80869.85169.74168.82275.10275.42075.61776.40077.85478.26678.67476.04675.88075.89175.71174.22673.43474.01371.98476.50677.15676.54877.21078.63578.57376.40375.55676.66476.08274.97774.36177.12978.00577.00877.95878.78078.04177.23576.06277.94377.33976.65677.703

4.7215.6634.8515.7906.1887.1532.8342.2782.5091.3201.7222.2540.4740.5811.154-0.743-1.454-1.576-2.616-4.022-2.732-2.744-3.143-3.353-4.621-4.459-4.103-5.564-5.159-6.871-7.932-8.584-9.613-8.983-9.295-9.523-10.511-9.906-9.914-11.782-11.807-12.900-14.121-14.815-15.337

63.6563.2562.7863.0563.8065.2260.5560.4758.1456.6556.6457.4855.3655.6354.1554.9954.8153.5853.2451.5051.9755.1354.7555.1456.1456.7859.1056.7857.2157.7158.6258.7559.5260.2259.1662.7465.0264.9165.1566.6866.5769.0771.8872.4071.91

HHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH

CCCCCOCONCCOCCONCCCCCCONCCOCONCCOCONCCOCONCCC

602760286029603060316032603360346035603660376038603960406041604260436044604560466047604860496050605160526053605460556056605760586059606060616062606360646065606660676068606960706071

CG2CONCACBOG1CG2CONCACBCG1CG2CONCDCACBCGCONCACBOGCONCACBOGCONCDCACBCGCONCA

VAL HVAL HVAL HTHR HTHR HTHR HTHR HTHR HTHR HTHR HVAL HVAL HVAL HVAL HVAL HVAL HVAL HPRO HPRO HPRO HPRO HPRO HPRO HPRO HSER HSER HSER HSER HSER HSER HSER HSER HSER HSER HSER HSER HPRO HPRO HPRO HPRO HPRO HPRO HPRO HARG HARG H

181181181182182182182182182182183183183183183183183184184184184184184184185185185185185185186186186186186186187187187187187187187188188

38.48939.88339.42441.08841.82643.27743.32243.89641.81241.96341.54341.50640.05639.49239.20141.96341.66542.71943.14343.10943.42543.02041.94240.78842.26541.17541.79643.10040.25839.05340.87540.14341.07042.40938.87237.75239.08340.34737.97038.55840.05036.92836.10137.00136.126

75.81278.37479.50877.98078.90279.12579.38480.29478.40377.22179.37479.12278.84577.60580.05380.37481.49480.17978.93481.27880.64079.17182.26781.90783.57384.53985.91785.93584.19784.03084.12983.77482.95183.05182.97583.44081.71481.04980.79579.48779.48781.34280.62582.66383.344

-15.979-15.003-15.152-15.536-16.431-15.950-14.540-16.730-17.877-18.160-18.794-20.231-20.658-19.968-20.320-20.976-20.600-22.083-22.681-22.974-24.339-24.249-23.160-23.284-23.196-23.307-23.523-22.948-24.482-24.357-25.669-26.880-27.779-27.294-26.564-26.720-26.142-25.882-25.903-25.379-25.685-24.911-24.368-24.664-23.714

72.8074.0474.0176.6179.8279.8780.8280.0981.4881.9083.4185.2884.9084.5484.5086.8786.4288.5488.2989.5989.0988.3290.9991.3992.3793.9293.7193.4595.3795.8296.7197.4597.2296.7398.1898.2398.6799.1298.8198.6499.0099.0699.2199.3599.40

HHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH

CCONCCOCCONCCCCCONCCCCCONCCOCONCCOCONCCCCCONC

607260736074607560766077607860796080608160826083608460856086608760886089609060916092609360946095609660976098609961006101610261036104610561066107610861096110611161126113611461156116

CBCGCDNECZNH1NH2CONCDCACBCGCONCACBOGCONCACBCGCDOE1OE2CONCACBOG1CG2CONCACBCG1CG2CO

ARG HARG HARG HARG HARG HARG HARG HARG HARG HPRO HPRO HPRO HPRO HPRO HPRO HPRO HSER HSER HSER HSER HSER HSER HGLU HGLU HGLU HGLU HGLU HGLU HGLU HGLU HGLU HTHR HTHR HTHR HTHR HTHR HTHR HTHR HVAL HVAL HVAL HVAL HVAL HVAL HVAL H

188188188188188188188188188189189189189189189189190190190190190190191191191191191191191191191192192192192192192192193193193193193193193

36.56735.44334.24834.58133.61232.42333.85636.18337.23034.99234.69533.73732.64833.29033.35432.20634.36034.10435.43335.18133.09831.93333.60232.70833.43834.40335.56536.43535.58632.26432.72331.30830.72429.27729.25328.44031.48731.91831.65932.10633.31933.15033.50630.96730.403

82.95982.30583.24784.32284.72684.15085.71784.86585.46385.48986.90984.75985.75287.12884.07483.73283.92283.25582.71181.69682.11482.21180.98979.88078.56578.66977.72778.04576.67379.93480.74779.04779.09178.62377.41079.67878.20577.10278.81178.05378.76180.27378.36977.95878.947

-22.300-21.498-21.305-20.364-19.521-19.552-18.659-23.879-24.085-23.825-23.868-23.700-23.292-23.140-25.015-25.264-25.894-27.163-27.684-28.655-26.993-27.357-26.451-26.132-26.415-27.596-27.379-26.581-28.012-24.669-23.876-24.329-22.994-23.105-23.863-23.840-22.002-22.313-20.824-19.668-19.062-19.171-17.610-18.664-18.214

99.6799.53100.0699.98100.11100.1699.9099.1899.8898.6198.4198.3798.2597.8298.6198.4998.7698.8899.51100.2098.5098.4398.1897.3498.1599.39100.16100.89100.3896.1895.9894.9693.7894.0594.2693.6692.5892.1890.8088.6088.0788.6987.6387.3887.20

HHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH

CCCNCNNCONCCCCCONCCOCONCCCCOOCONCCOCCONCCCCCO

611761186119612061216122612361246125612661276128612961306131613261336134613561366137613861396140614161426143614461456146614761486149615061516152615361546155615661576158615961606161

NCACBOG1CG2CONCACOCBSGNCACBCGOD1ND2CONCACBCG1CG2CONCACBCONCACBCGCD2ND1CE1NE2CONCD

THR HTHR HTHR HTHR HTHR HTHR HTHR HCYS HCYS HCYS HCYS HCYS HCYS HASN HASN HASN HASN HASN HASN HASN HASN HVAL HVAL HVAL HVAL HVAL HVAL HVAL HALA HALA HALA HALA HALA HHIS HHIS HHIS HHIS HHIS HHIS HHIS HHIS HHIS HHIS HPRO HPRO H

194194194194194194194195195195195195195196196196196196196196196197197197197197197197198198198198198199199199199199199199199199199200200

30.58729.49228.37027.81627.26029.95530.67229.54430.05128.84627.74830.82529.97429.06627.98027.91528.40629.52527.50128.28129.21727.31827.42927.17927.22928.25326.38125.21326.74725.74925.84125.92127.02424.82624.77624.25524.32925.31123.28223.66924.89423.78022.63724.22625.632

76.70976.47875.81376.77375.33975.58574.61375.71674.78474.04374.58775.60075.84372.78071.87270.60670.87571.16270.82671.39970.69671.58671.32772.62972.35773.64370.34570.53069.31868.43767.20568.20168.15167.95367.80469.07368.89468.37169.15068.91168.39166.70567.02665.44165.150

-18.396-17.489-18.285-19.185-17.346-16.355-16.553-15.093-14.145-13.572-13.422-13.095-11.518-13.183-12.865-13.774-15.164-15.381-16.106-11.561-11.342-10.735-9.318-8.554-7.046-9.009-8.905-9.240-8.145-7.608-8.296-6.135-5.641-5.469-4.064-3.271-1.791-1.013-0.9520.3020.287-3.971-3.897-4.035-4.215

85.5483.6583.8684.3582.9982.1782.5580.0878.1276.0874.8179.6382.8974.4072.9572.1571.8368.9973.5072.4772.1071.6970.2269.3667.9568.7169.7570.3568.5767.6767.3067.3266.2367.3868.4767.9667.2366.8766.4467.1866.3069.1369.6769.9869.33

HHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH

NCCOCCONCCOCSNCCCONCONCCCCCONCCCONCCCCNCNCONC

616261636164616561666167616861696170617161726173617461756176617761786179618061816182618361846185618661876188618961906191619261936194619561966197619861996200620162026203620462056206

CACBCGCONCACBCONCACBOGCONCACBOGCONCACBOG1CG2CONCACBCGCDCENZCONCACBCG1CG2CO

PRO HPRO HPRO HPRO HPRO HALA HALA HALA HALA HALA HSER HSER HSER HSER HSER HSER HSER HSER HSER HSER HSER HSER HTHR HTHR HTHR HTHR HTHR HTHR HTHR HLYS HLYS HLYS HLYS HLYS HLYS HLYS HLYS HLYS HVAL HVAL HVAL HVAL HVAL HVAL HVAL H

200200200200200201201201201201202202202202202202203203203203203203204204204204204204204205205205205205205205205205206206206206206206206

23.39224.40125.70822.50321.33323.03222.18422.89020.82619.92020.71619.44619.66020.29118.95718.18919.46418.89217.41317.28419.00018.06520.14920.30620.92020.04220.96021.19222.17320.87021.76821.72922.42823.76124.37725.87321.51020.39222.54622.50922.55622.55021.38023.69424.827

64.22263.06463.63464.26164.01664.64464.60765.10965.31864.86566.39067.13668.59569.31567.12667.97366.18565.96965.52564.16867.24967.64567.85869.11670.10170.16171.52768.89668.18769.53969.54568.17268.03168.92768.62868.73270.85171.12171.70173.04674.05675.54073.84773.33872.842

-3.910-3.673-4.023-2.707-2.771-1.571-0.3790.764-0.5290.034-1.286-1.396-0.939-2.024-2.831-3.318-3.560-4.827-4.606-4.052-5.719-6.453-5.688-6.344-5.307-4.206-5.762-7.564-7.512-8.645-9.766-10.481-11.878-12.188-13.676-13.750-10.601-11.148-10.571-11.125-10.024-10.675-9.119-12.032-11.783

70.7570.8771.2572.0472.6472.8672.9872.3873.6173.8074.3275.6476.1676.2576.1176.1876.7677.5477.3577.6077.7978.1377.8578.9579.0680.4579.1879.5079.8580.1881.6481.7783.9485.6586.6187.1582.2982.6482.7183.1183.1983.8582.8383.7083.58

HHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH

CCCCONCCCONCCOCONCCOCONCCOCCONCCCCCNCONCCCCCO

620762086209621062116212621362146215621662176218621962206221622262236224622562266227622862296230623162326233623462356236623762386239624062416242624362446245624662476248624962506251

NCACBCGOD1OD2CONCACBCONCACBCGCDCENZCONCACBCG2CG1CD1CONCACBCONCACBCONCACBCO

ASP HASP HASP HASP HASP HASP HASP HASP HALA HALA HALA HALA HALA HLYS HLYS HLYS HLYS HLYS HLYS HLYS HLYS HLYS HILE HILE HILE HILE HILE HILE HILE HILE HALA HALA HALA HALA HALA HALA HALA HALA HALA HALA HALA HALA HALA HALA HALA H

207207207207207207207207208208208208208209209209209209209209209209210210210210210210210210211211211211211212212212212212213213213213213

23.42224.46224.27024.34225.43623.38024.45623.50125.48425.56325.81126.57227.79325.99726.70725.69426.28325.22725.83724.79627.40126.83228.69529.43830.91831.65431.08830.40929.19229.62328.42327.95726.98929.10529.78729.27630.29029.84430.48031.34529.66029.75029.40731.15431.731

74.13474.53273.85872.30271.77371.53876.04476.60176.71078.16078.89978.52878.19379.26579.88180.14180.98081.36281.99282.69981.18982.07181.27682.49482.13683.15480.75180.64983.57283.48584.59485.59586.52986.40985.99787.62988.51888.92289.76489.83590.79392.01391.66192.61593.023

-13.075-14.042-15.435-15.384-15.662-15.103-14.123-14.580-13.580-13.722-12.475-14.793-14.774-15.730-16.848-17.964-19.098-20.136-21.392-22.135-16.447-15.816-16.805-16.508-16.427-15.536-15.794-14.424-17.570-18.713-17.155-18.107-17.376-18.708-19.636-18.171-18.725-20.131-17.861-16.998-18.151-17.360-15.911-17.425-16.428

84.9586.3886.9988.6388.9889.5287.0786.9587.9088.6687.8489.6689.7090.6091.3491.1691.0190.8390.5389.4491.7891.5592.6493.4992.0991.7191.2590.2595.0195.1696.5297.9697.8599.0899.14100.17101.26101.45101.96102.21103.01104.14104.00105.06105.39

HHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH

NCCCOOCONCCCONCCCCCNCONCCCCCCONCCCONCCCONCCCO

625262536254625562566257625862596260626162626263626462656266626762686269627062716272627362746275627662776278627962806281628262836284628562866287628862896290629162926293629462956296

OXTOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOO

ALA HHOH WHOH WHOH WHOH WHOH WHOH WHOH WHOH WHOH WHOH WHOH WHOH WHOH WHOH WHOH WHOH WHOH WHOH WHOH WHOH WHOH WHOH WHOH WHOH WHOH WHOH WHOH WHOH WHOH WHOH WHOH WHOH WHOH WHOH WHOH WHOH WHOH WHOH WHOH WHOH WHOH WHOH WHOH WHOH W

2131234567891011121314151618192021222324252627282930313233343536373839404142434445

31.76648.04056.25553.94326.43035.13132.11651.77644.76739.73551.94338.74746.18158.42843.55457.41561.27048.45953.91656.55832.80847.84736.92526.21445.64444.85641.93425.28149.89229.79238.27227.85857.79931.79538.42546.86036.02841.45261.27758.22645.00032.22024.26843.87045.208

92.71727.60630.91067.19518.33545.61035.08759.86437.32152.97557.48431.22862.16347.23836.44461.70151.28741.31029.66371.37727.12362.03677.94442.19456.04670.99061.98634.50262.41166.37658.08455.05463.67268.78931.42766.95769.39374.0298.82038.91161.69433.15956.22551.81148.980

-18.478-7.533-4.462-8.118-11.581-13.929-8.53411.192-4.124-5.90612.566-1.6510.2964.389-2.05412.62712.253-2.5767.818-0.532-0.609-10.526-1.83814.0549.9661.971-0.999-1.348-6.9805.878-4.321-6.230-12.2430.185-8.589-9.197-9.0442.5818.3795.1653.280-1.482-2.60412.171-4.712

105.7143.4955.4754.9844.4249.4056.8342.0242.7861.0239.4743.6956.4048.7945.5741.4967.5248.8148.6048.1444.9363.9750.6263.3842.5172.8278.2661.2759.5052.9065.0156.0259.4863.0360.6254.2662.2257.0345.1758.2467.7754.5175.8743.9441.05

HWWWWWWWWWWWWWWWWWWWWWWWWWWWWWWWWWWWWWWWWWWWW

OOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOO

629762986299630063016302630363046305630663076308630963106311631263136314631563166317631863196320632163226323632463256326632763286329633063316332633363346335633663376338633963406341

OOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOO

464748495051525354555657585960616263646566676869707273747576777879808182838485868788899091

51.08645.73540.67047.85527.97526.64940.33226.88946.33238.28652.67842.01034.53035.89232.19045.52745.91338.31054.61139.89844.93822.64440.73958.60423.02136.56236.15646.57563.10627.28342.11956.21349.59319.20562.46963.94251.55956.70256.70338.70355.18053.09842.57957.34161.045

54.35454.90936.69148.29120.73637.01112.1844.62635.28611.97629.08349.51460.32362.0308.37838.44956.89229.70860.45713.40265.75047.30060.46238.40150.25676.33230.94145.89860.74311.65612.90674.27117.07450.43645.07560.52922.88418.71713.17045.09062.43634.49352.36968.46340.263

-7.83012.584-0.514-6.195-9.2263.912-6.970-22.0124.217-5.012-13.03712.09012.8496.806-14.29811.020-4.556-4.57912.3804.4291.699-3.32713.58916.276-0.3310.2285.240-6.2135.288-26.940-15.8120.2104.7316.98115.4962.662-12.355-5.348-0.33918.422-12.094-1.712-5.0684.885-1.253

52.3447.5340.0347.9861.3954.8960.2650.2942.3547.6274.0948.8051.8767.8957.4242.8349.1559.2748.3856.1477.4178.4957.6063.2564.4359.7754.6651.0365.6364.6969.7549.0751.2265.5857.0565.5653.7760.7753.6649.8962.4240.2963.3563.0961.58

WWWWWWWWWWWWWWWWWWWWWWWWWWWWWWWWWWWWWWWWWWWWW

OOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOO

634263436344634563466347634863496350635163526353635463556356635763586359636063616362636363646365636663676368636963706371637263736374637563766377637863796380638163826383638463856386

OOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOO

92939495969899100102103104106107108110111112113114115116117118119120121122123124125126127128129130131132133134136137138139140142

35.56756.06942.08230.01138.43650.32258.46444.70023.65637.41139.63728.71744.18045.96650.43160.16753.60024.14524.87651.64337.62754.09327.16251.28649.20228.41354.14942.92455.16830.28528.49829.59136.17242.25846.13827.63045.17720.60629.09351.10021.22339.90822.63055.36825.657

69.26124.45814.76960.16148.43024.77655.47436.69417.78150.14814.79435.02752.42631.34424.44346.65425.36120.68623.0403.46761.51737.31950.14463.60762.36138.64122.50249.9508.79412.1901.56665.60656.7638.23051.84660.43468.25552.4179.72180.70352.94148.60941.25243.47965.193

-15.1914.847-10.703-0.58617.977-13.19213.643-6.969-5.182-8.219-13.739-8.77014.92810.7719.057-5.1729.729-4.121-17.5963.8134.930-7.747-5.2588.4427.87911.608-12.184-5.3290.302-25.537-1.7118.39014.794-13.60416.64019.677-15.2824.041-4.723-12.10219.57313.4283.257-8.878-1.065

63.5855.6176.0856.5968.4658.2851.6670.5658.0752.2466.8279.0053.1264.1657.1082.3580.8582.3566.2469.6061.3563.6963.2455.4056.2258.6858.0455.7156.1955.2065.3377.2066.6765.2054.6559.0383.6968.3997.1369.5789.9154.7775.5750.9356.79

WWWWWWWWWWWWWWWWWWWWWWWWWWWWWWWWWWWWWWWWWWWWW

OOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOO

638763886389639063916392639363946395639663976398639964006401640264036404640564066407640864096410641164126413641464156416641764186419642064216422642364246425642664276428642964306431

OOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOO

143144145146147148149150151152153154155156157158159160161162163164165166167168169170171172173174175177180181182183184185186187188191192

21.04151.58332.28641.98534.84648.12559.94461.67153.97333.05440.31749.62840.94939.01942.10248.29949.39245.97462.46362.31448.70826.59427.65027.59443.45038.12227.12962.11446.57848.22870.19764.00442.69618.05915.35535.27437.7344.39825.72655.96752.63542.18754.08039.37330.145

43.3395.155-14.72768.50377.58934.52818.44443.98839.89813.12733.41968.07612.53124.89851.1464.48930.41871.34457.8423.85328.59022.89457.27860.02054.03059.23839.3019.62259.16152.4422.7532.450-4.99023.62421.66418.20720.0589.99662.2965.96932.45861.26767.80449.81748.697

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79.1668.0782.0384.6887.0764.1080.9773.5763.0146.5464.6966.4157.3167.9468.4656.5658.5768.3568.9372.8570.4672.6675.2762.7685.0856.8768.0950.8677.6451.1887.4969.2872.72101.3068.2681.1776.6573.2368.0863.2864.3063.6373.0773.9667.43

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^a根据表6及7中所示的Chothia编号系统(Al-Lazikani等人，Jour.Mol.Biol. 273：927-948，1997)分别编号轻链(L)和重链(H)的氨基酸残基。IL-13(I)的氨基酸残基编号如SEQ ID NO：4所示(图2B)。IL-13Rα1的氨基酸残基编号如SEQ ID NO：12所示(图14)。

b各栏根据Protein Data Bank Format，2.2版标注。

其他实施方案见权利要求书。

Claims

1.晶体抗体，其中所述抗体包括抗IL-13抗体或抗IL-13抗体的Fab片段。

2.权利要求1的晶体抗体，其中晶体抗体的空间群为P2₁2₁2₁。

3.权利要求1或2中任一项的晶体抗体，其中晶体抗体的晶胞大小为a＝54.4，b＝98.0，c＝108.5，且α＝β＝γ＝90°。

4.权利要求1-3中任一项的晶体抗体，其中抗体来自哺乳动物。

5.权利要求1-4中任一项的晶体抗体，其中抗体晶体来自小鼠、大鼠、兔或山羊。

6.权利要求1-5中任一项的晶体抗体，还含有结合于所述抗体的IL-13多肽。

7.权利要求6的晶体抗体，其中还含有结合于IL-13多肽的IL-13Rα1多肽。

8.权利要求1-7中任一项的晶体抗体，其中抗体含有包括氨基酸序列SEQ ID NO：1的多肽。

9.权利要求1-8中任一项的晶体抗体，其中抗体含有包括氨基酸序列SEQ ID NO：2的多肽。

10.权利要求1-9中任一项的晶体抗体，其中抗体为单克隆抗体。

11.权利要求1-10中任一项的晶体抗体，其中抗体为mAb13.2。

12.权利要求1-11中任一项的晶体抗体，其中抗体为mAb13.2Fab片段。

13.权利要求1-12中任一项的晶体抗体，其中抗体能与IL-13上与IL-4R多肽体内结合的区域结合。

14.权利要求1-13中任一项的晶体抗体，其中晶体抗体能衍射X射线至分辨率至少为3.5_。

15.权利要求1-14中任一项的晶体抗体，其中晶体抗体含有表10的结构坐标+/-不大于1.5_的α碳原子的均方根差。

16.权利要求1-15中任一项的晶体抗体，其中：

抗体轻链含有SEQ ID NO：1的氨基酸序列；

抗体重链含有SEQ ID NO：2的氨基酸序列；且

晶体抗体衍射X射线至分辨率至少为3.5_。

17.包含抗体的晶体组合物，其中所述抗体包括抗IL-13抗体或抗IL-13抗体的Fab片段。

18.权利要求17的晶体组合物，还含有至少一个水分子。

19.权利要求17或18任一项的晶体组合物，还含有盐或锌。

20.权利要求17-19中任一项的晶体组合物，还含有结合于所述抗IL-13抗体或Fab片段的IL-13多肽。

21.权利要求20的晶体组合物，还含有结合于所述IL-13多肽的IL-13Rα1多肽。

22.晶体复合物，含有：

IL-13多肽；和

抗体，

其中抗体包括抗IL-13抗体或抗IL-13抗体的Fab片段。

23.权利要求22的晶体复合物，其中晶体复合物的空间群为P2₁3。

24.权利要求22或23中任一项的晶体复合物，其中晶体复合物的晶胞大小为a＝b＝c＝125.3_，且α＝β＝γ＝90°。

25.权利要求22-24中任一项的晶体复合物，其中抗体来自哺乳动物。

26.权利要求22-25中任一项的晶体复合物，其中抗体来自小鼠。

27.权利要求22-26中任一项的晶体复合物，其中IL-13多肽来自哺乳动物。

28.权利要求22-27中任一项的晶体复合物，其中IL-13多肽来自人。

29.权利要求22-28中任一项的晶体复合物，其中抗体含有包括氨基酸序列SEQ ID NO：1的多肽。

30.权利要求22-29中任一项的晶体复合物，其中抗体含有包括氨基酸序列SEQ ID NO：2的多肽。

31.权利要求22-30中任一项的晶体复合物，其中抗体为单克隆抗体。

32.权利要求22-31中任一项的晶体复合物，其中抗体为mAb13.2。

33.权利要求22-32中任一项的晶体复合物，其中抗体为mAb13.2Fab片段。

34.权利要求22-33中任一项的晶体复合物，其中抗体能与IL-13多肽上与IL-4R多肽体内结合的区域结合。

35.权利要求22-34中任一项的晶体复合物，其中IL-13多肽中含有结合IL-4R多肽的区域。

36.权利要求22-35中任一项的晶体复合物，其中IL-13多肽包括氨基酸序列SEQ ID NO：4。

37.权利要求22-36中任一项的晶体复合物，其中抗体与SEQ IDNO：4氨基酸序列所定义的Ser7、Thr8、Ala9、Glu12、Leu48、Glu49、Ile52、Asn53、Arg65、Ser68、Gly69、Phe70、Cys71、Pro72、His73、Lys74和Arg86中的一个或多个残基相互作用。

38.权利要求22-37中任一项的晶体复合物，其中IL-13多肽与SEQID NO：1氨基酸序列所定义的Asn31、Tyr32、Lys34、Arg54、Asn96、Asp98和Trp100以及SEQ ID NO：2氨基酸序列所定义的Ile30、Ser31、Ala33、Trp47、Ser50、Ser52、Ser53、Tyr58、Leu98、Asp99、Gly100、Tyr101、Tyr102和Phe103中的一个或多个残基相互作用。

39.权利要求22-38中任一项的晶体复合物，其中晶体复合物能衍射X射线至分辨率至少为3.5_。

40.权利要求22-39中任一项的晶体复合物，其中晶体复合物含有表11的结构坐标+/-不大于1.5_的α碳原子的均方根差。

41.权利要求22-40中任一项的晶体复合物，还含有IL-13Rα1多肽。

42.晶体复合物，包括：

IL-13Rα1多肽；和

IL-13多肽。

43.权利要求42的晶体复合物，其中晶体复合物的空间群为I4。

44.权利要求42或43的任一项的晶体复合物，其中晶体复合物的晶胞大小为a＝b＝164.9_，c＝74.8_，且α＝β＝γ＝90°。

45.权利要求42、43或44的任一项的晶体复合物，还含有抗体，

其中所述抗体包括抗IL-13抗体或抗IL-13抗体的Fab片段。

46.权利要求45的晶体复合物，其中抗体来自哺乳动物。

47.权利要求45或46中任一项的晶体复合物，其中抗体来自小鼠。

48.权利要求42-47中任一项的晶体复合物，其中IL-13多肽来自哺乳动物。

49.权利要求42-48中任一项的晶体复合物，其中IL-13多肽来自人。

50.权利要求45或46中任一项的晶体复合物，其中抗体为单克隆抗体。

51.权利要求45或46中任一项的晶体复合物，其中抗体为mAb13.2。

52.权利要求45或46中任一项的晶体复合物，其中抗体为mAb13.2Fab片段。

53.权利要求45或46中任一项的晶体复合物，其中抗体与IL-13多肽上体内结合IL-4R多肽的区域结合。

54.权利要求42-53中任一项的晶体复合物，其中IL-13多肽中含有与IL-4R多肽结合的区域。

55.权利要求42-54中任一项的晶体复合物，其中IL-13Rα1多肽来自哺乳动物。

56.权利要求42-55中任一项的晶体复合物，其中IL-13Rα1多肽来自人。

57.权利要求42-56中任一项的晶体复合物，其中IL-13多肽包括SEQ ID NO：4的氨基酸序列。

58.权利要求42-57中任一项的晶体复合物，其中IL-13Rα1多肽包括SEQ ID NO：12的氨基酸序列。

59.权利要求44或46中任一项的晶体复合物，其中抗体与SEQ IDNO：4氨基酸序列所定义的Ser7、Thr8、Ala9、Glu12、Leu48、Glu49、Ile52、Asn53、Arg65、Ser68、Gly69、Phe70、Cys71、Pro72、His73、Lys74和Arg86中的一个或多个残基相互作用。

60.权利要求45或46中任一项的晶体复合物，其中IL-13多肽与SEQ ID NO：1氨基酸序列所定义的Asn31、Tyr32、Lys34、Arg54、Asn96、Asp98和Trp100以及SEQ ID NO：2氨基酸序列所定义的Ile30、Ser31、Ala33、Trp47、Ser50、Ser52、Ser53、Tyr58、Leu98、Asp99、Gly100、Tyr101、Tyr102和Phe103中的一个或多个残基相互作用。

61.权利要求42-60中任一项的晶体复合物，其中IL-13多肽与SEQID NO：12氨基酸序列所定义的Ile254、Ser255、Arg256、Lys318、Cys320、Tyr321、Lys76、Lys77、Ile78和Ala79中的一个或多个残基相互作用。

62.权利要求42-59中任一项的晶体复合物，其中IL-13Rα1多肽与SEQ ID NO：4氨基酸序列所定义的Arg11、Glu12、Leu13、Ile14、Glu15、Thr88、Lys89、Ile90、Glu91、Lys104、Lys105、Leu106、Phe107和Arg108中的一个或多个残基相互作用。

63.权利要求42-62中任一项的晶体复合物，其中晶体复合物能衍射X射线至分辨率至少为3.5_。

64.权利要求42-63中任一项的晶体复合物，其中晶体复合物含有表12的结构坐标+/-不大于1.5_的α碳原子的均方根差。

65.利用抗体三维模型设计与IL-13多肽相互作用的物质的方法，

其中抗体包括抗IL-13抗体或抗IL-13抗体的Fab片段。

66.权利要求65的方法，其中的三维模型包括抗体的CDR。

67.权利要求65或66中任一项的方法，其中抗体为抗IL-13抗体的Fab片段。

68.权利要求65-67中任一项的方法，其中抗体含有包括氨基酸序列SEQ ID NO：1的轻链多肽以及包括氨基酸序列SEQ ID NO：2的重链多肽。

69.权利要求65-68中任一项的方法，其中抗体为mAb13.2。

70.权利要求65-69中任一项的方法，其中抗体为mAb13.2Fab片段。

71.权利要求65-70中任一项的方法，其中三维模型包括抗体原子的结构坐标。

72.权利要求71的方法，其中结构坐标是经试验确定的结构坐标。

73.权利要求65-72中任一项的方法，其中三维模型包括从由SEQID NO：1氨基酸序列所定义的Asn31、Tyr32、Lys34、Arg54、Asn96、Asp98和Trp100以及SEQ ID NO：2氨基酸序列所定义的Ile30、Ser31、Ala33、Trp47、Ser50、Ser52、Ser53、Tyr58、Leu98、Asp99、Gly100、Tyr101、Tyr102和Phe103氨基酸的原子组成的组中选择的原子的结构坐标。

74.权利要求65-73中任一项的方法，其中物质与IL-13多肽上与IL-4R多肽体内结合的区域结合。

75.权利要求74的方法，其中IL-4R多肽为IL-4Rα多肽。

76.权利要求65-75中任一项的方法，其中三维模型包括结合于抗体的IL-13多肽。

77.权利要求76的方法，其中三维模型还包括结合于IL-13多肽的IL-13Rα1多肽。

78.利用IL-13多肽三维模型设计与IL-13多肽相互作用的物质的方法。

79.权利要求78的方法，其中三维模型还包括结合于IL-13多肽的抗体，所述抗体包括抗IL-13抗体或抗IL-13抗体的Fab片段。

80.权利要求79的方法，其中三维模型包括抗体原子的结构坐标。

81.权利要求78-807中任一项的方法，其中三维模型包括IL-13多肽上与IL-4R多肽体内结合的区域。

82.权利要求78-81中任一项的方法，其中所述物质抑制IL-13多肽与IL-4R多肽的结合。

83.权利要求75-79中任一项的方法，其中三维模型包括IL-13多肽原子的结构坐标。

84.权利要求71的方法，其中结构坐标经试验确定。

85.权利要求83或84中任一项的方法，其中的结构坐标为表11+/-不大于1.5_的α碳原子的均方根差。

86.权利要求78-85中任一项的方法，其中三维模型包括从由氨基酸序列SEQ ID NO：4所定义的IL-13多肽中Glu49、Asn53、Ser68、Gly69、Phe70、Cys71、Pro72、His73、Lys74和Arg86氨基酸的原子组成的组中选择的原子的结构坐标。

87.权利要求78-86中任一项的方法，其中三维模型还包括结合于IL-13多肽的IL-13Rα1多肽。

88.权利要求87的方法，其中三维模型包括IL-13Rα1多肽原子的结构坐标。

89.利用结合于IL-13Rα1多肽的IL-13多肽三维模型设计与IL-13多肽相互作用的物质的方法。

90.权利要求89的方法，其中三维模型还包括结合于IL-13多肽的抗体，所述抗体包括抗IL-13抗体或抗IL-13抗体的Fab片段。

91.权利要求89或90中任一项的方法，其中所述物质抑制IL-13多肽与IL-4R多肽的结合。

92.权利要求89-91中任一项的方法，其中三维模型包括IL-13多肽和IL-13Rα1多肽原子的结构坐标。

93.权利要求92的方法，其中结构坐标经试验确定。

94.权利要求92或93中任一项的方法，其中的结构坐标为表12+/-不大于1.5_的α碳原子的均方根差。

95.方法，包括：

利用含IL-13多肽的晶体复合物的三维结构进行合理的药物设计，来选择物质；

将所述物质与IL-13多肽接触；和

检测所述物质与IL-13多肽结合的能力。

96.权利要求95的方法，其中三维模型还包括结合于IL-13多肽的抗体，所述抗体包括抗IL-13抗体或抗IL-13抗体的Fab片段。

97.权利要求96的方法，其中抗IL-13抗体或抗IL-13抗体的Fab片段能与IL-13多肽上的IL-4R多肽与之体内结合的位点结合。

98.权利要求95-97中任一项的方法，其中通过计算机建模选择所述物质。

99.权利要求95-98中任一项的方法，其中的结构坐标为表11+/-不大于1.5_的α碳原子的均方根差。

100.权利要求95-99中任一项的方法，其中三维结构的晶体复合物还包括结合于IL-13多肽的IL-13Rα1多肽。

101.权利要求95-100中任一项的方法，其中的结构坐标为表12+/-不大于1.5_的α碳原子的均方根差。

102.权利要求95-101中任一项的方法，还包括获取所述物质。

103.权利要求95-102中任一项的方法，还包括：

获取含有IL-13多肽和所述物质的增补晶体复合物；

确定所述增补晶体复合物的三维结构；

利用所述增补晶体复合物的三维结构进行合理的药物设计，来选择第二物质；

将所述第二物质与IL-13多肽接触；和

检测所述第二物质与IL-13多肽结合的能力。

104.权利要求103的方法，其中通过计算机建模选择第二物质。

105.权利要求103或104中任一项的方法，还包括检测第二物质抑制IL-13活性的能力。

106.方法，包括：

将IL-13多肽与抗体接触以形成组合物；和

使所述组合物结晶以形成晶体复合物，其中抗体结合于IL-13多肽，

其中所述抗体包括抗IL-13抗体或抗IL-13抗体的Fab片段，且所述晶体复合物能衍射X射线，分辨率至少约3.5_。

107.权利要求106的方法，其中所述方法包括使用蒸汽扩散法。

108.权利要求106或107中任一项的方法，其中抗体为mAb13.2。

109.权利要求106-108中任一项的方法，其中抗体为mAb13.2Fab片段。

110.方法，包括：

将IL-13多肽与抗体和IL-13Rα1多肽接触以形成组合物；

使所述组合物结晶以形成晶体复合物，其中所述抗体和IL-13Rα1多肽各自结合于IL-13多肽，

111.权利要求110的方法，其中所述方法包括使用蒸汽扩散法。

112.权利要求110-111中任一项的方法，其中抗体为mAb13.2。

113.权利要求110-112中任一项的方法，其中抗体为mAb13.2Fab片段。

114.软件系统，其中包括这样的指令，所述指令可令计算机系统：

接受有关结合于抗体的IL-13多肽结构的信息，所述抗体包括抗IL-13抗体或抗IL-13抗体的Fab片段；

接受有关候选物质的信息；并

确定所述候选物质与IL-13多肽的结合特性，

其中结合特性的确定是基于有关IL-13多肽结构的信息以及有关候选物质的信息。

115.权利要求114的软件系统，其中结合于抗体的IL-13多肽结构为晶体结构。

116.权利要求115的软件系统，其中晶体结构包括表11的结构坐标+/-不大于1.5_的α碳原子的均方根差。

117.权利要求106-108的任一项的软件系统，其中结合于抗体的IL-13多肽结构还包括结合于IL-13多肽的IL-13Rα1多肽。

118.权利要求117的软件系统，其中结合于抗体的IL-13多肽以及结合于IL-13多肽的IL-13Rα1多肽的结构为晶体结构。

119.权利要求118的软件系统，其中晶体结构包括表12的结构坐标+/-不大于1.5_的α碳原子的均方根差。

120.权利要求114-119中任一项的软件系统，还包括指令以使计算机系统：

应用来自数据库的与候选物质相关的信息；和

鉴定数据库中能结合IL-13多肽的候选物质，

其中基于有关IL-13多肽结构的信息以及有关候选物质的信息进行鉴定。

121.权利要求114-120中任一项的软件系统，还包括使计算机对候选物质与IL-13多肽的结合特性进行建模的指令。

122.存储于计算机可读介质的包括大量指令的计算机程序，当所述指令被一个或多个处理器执行时，会使所述一个或多个处理器：

接受有关候选物质的信息；和

确定所述候选物质与IL-13多肽的结合特性，

123.权利要求122的计算机程序，其中结合于抗体的IL-13多肽结构还包括结合于IL-13多肽的IL-13Rα1多肽。

124.方法，包括：

接受有关结合于抗体的IL-13多肽结构的信息，所述抗体包括抗IL-13抗体或抗IL-13抗体的Fab片段；和

对IL-13多肽与候选物质的结合特性进行建模，

其中所述方法由软件系统执行。

125.权利要求124的方法，其中结合于抗体的IL-13多肽结构还包括结合于IL-13多肽的IL-13Rα1多肽。

126.权利要求124或125中任一项的方法，还包括应用来自数据库的信息鉴定能结合IL-13多肽的候选物质，

127.存储于计算机可读介质的包括大量指令的计算机程序，当所述指令被一个或多个处理器执行时，会使所述一个或多个处理器：

接受有关结合于抗体的IL-13多肽结构的信息，所述抗体包括抗IL-13抗体或抗IL-13抗体的Fab片段；且

对IL-13多肽与候选物质的结合特性进行建模。

128.权利要求127的计算机程序，其中结合于抗体的IL-13多肽结构还包括结合于IL-13多肽的IL-13Rα1多肽。

129.权利要求127或128中任一项的计算机程序，还包括指令以使一个或多个处理器：

应用来自数据库的与候选物质相关的信息；和

鉴定数据库中能结合IL-13多肽的候选物质，

130.权利要求127-129中任一项的计算机程序，还包括使一个或多个处理器对候选物质与IL-13多肽的结合特性进行建模的指令。

131.软件系统，包括指令以使计算机系统：

接受有关结合于抗体的IL-13多肽结构的信息，所述抗体为抗IL-13抗体或抗IL-13抗体的Fab片段；且

对IL-13多肽与候选物质的结合特性进行建模。

132.权利要求131的方法，其中结合于抗体的IL-13多肽结构还包括结合于IL-13多肽的IL-13Rα1多肽。

133.晶体抗体，所述抗体能够结合IL-13多肽上的IL-4R多肽与之体内结合的位点。

134.包含抗体的晶体组合物，其中所述抗体能结合IL-13多肽上的IL-4R多肽与之体内结合的位点。

135.晶体复合物，包括：

IL-13多肽；和

抗体，

其中所述抗体能够结合IL-13多肽上的IL-4R多肽与之体内结合的位点。

136.晶体复合物，包括：

IL-13多肽；

IL-13Rα1多肽；和

抗体，

137.方法，包括：

利用抗体的三维模型设计与IL-13多肽相互作用的物质，

138.权利要求137的方法，其中三维模型包括抗体原子的结构坐标。

139.方法，包括：

将IL-13多肽与抗体接触以形成组合物；和

使所述组合物结晶以形成晶体复合物，其中所述抗体结合于IL-13多肽，

其中所述抗体能够结合IL-13多肽上的IL-4R多肽与之体内结合的位点，且所述晶体复合物能衍射X射线，分辨率至少约3.5_。

140.方法，包括：

将IL-13多肽与抗体和IL-13Rα1多肽接触以形成组合物；和

使所述组合物结晶以形成晶体复合物，其中抗体和IL-13Rα1多肽各自结合于IL-13多肽，

其中所述抗体能够结合IL-13多肽上的IL-4R多肽与之体内结合的位点，且所述晶体复合物能衍射X射线，达到至少约3.5_的分辨率。

141.软件系统，包括指令以使计算机系统：

接受有关结合于抗体的IL-13多肽结构的信息，所述抗体能够结合IL-13多肽上的IL-4R多肽与之体内结合的位点；

接受有关候选物质的信息；和

确定所述候选物质与IL-13多肽的结合特性，

其中所述结合特性的确定基于有关IL-13多肽结构的信息以及有关候选物质的信息。

142.权利要求141的软件系统，其中结合于抗体的IL-13多肽结构还包括结合于IL-13多肽的IL-13Rα1多肽。

143.存储于计算机可读介质的包括大量指令的计算机程序，当所述指令被一个或多个处理器执行时，使所述一个或多个处理器：

接受有关候选物质的信息；和

确定所述候选物质与IL-13多肽的结合特性，

其中结合特性的确定基于有关IL-13多肽结构的信息以及有关候选物质的信息。

144.权利要求143的计算机程序，其中结合于抗体的IL-13多肽结构还包括结合于IL-13多肽的IL-13Rα1多肽。

145.方法，包括：

接受有关结合于抗体的IL-13多肽结构的信息，所述抗体能够结合IL-13多肽上的IL-4R多肽与之体内结合的位点；和

对IL-13多肽与候选物质的结合特性进行建模，

其中所述方法由软件系统执行。

146.权利要求145的方法，其中结合于抗体的IL-13多肽结构还包括结合于IL-13多肽的IL-13Rα1多肽。

147.存储于计算机可读介质的包括大量指令的计算机程序，当所述指令被一个或多个处理器执行时，使所述一个或多个处理器：

对IL-13多肽与候选物质的结合特性进行建模。

148.权利要求147的计算机程序，其中结合于抗体的IL-13多肽结构还包括结合于IL-13多肽的IL-13Rα1多肽。

149.软件系统，包括指令以使计算机系统：

对IL-13多肽与候选物质的结合特性进行建模。

150.权利要求149的软件系统，其中结合于抗体的IL-13多肽结构还包括结合于IL-13多肽的IL-13Rα1多肽。

151.调节受试者中IL-13活性的方法，包括：

利用合理的药物设计选择能调节IL-13活性的物质；和

对受试者施用治疗有效量的所述物质。

152.权利要求151的方法，其中合理的药物设计包括使用包含IL-13多肽的晶体复合物的三维结构。

153.权利要求152的方法，其中晶体复合物还包括抗体，所述抗体为抗IL-13抗体或抗IL-13抗体的Fab片段。

154.权利要求152或153的任一项的方法，其中晶体复合物还包括抗体，所述抗体能结合IL-13多肽上的IL-4R多肽与之体内结合的位点。

155.权利要求152-154的任一项的方法，其中晶体复合物还包括IL-13Rα1多肽。

156.治疗患有IL-13活性相关疾病的受试者的方法，包括：

利用合理的药物设计选择能影响IL-13活性的物质；和

对受试者施用治疗有效量的所述物质。

157.权利要求156的方法，其中疾病为哮喘。

158.权利要求156或157中的任一项的方法，其中疾病为过敏性哮喘或非过敏性哮喘。

159.权利要求156的方法，其中疾病包括至少一种选自癌症、气道炎症、嗜酸性粒细胞增多症、纤维化、过量粘液产生、皮肤、胃肠道器官、血管或结缔组织炎症性疾病以及皮肤、胃肠道器官、血管或结缔组织自身免疫性疾病的疾病。

160.权利要求156的方法，其中疾病包括至少一种选自慢性阻塞性肺病、囊性纤维化、肺纤维化、过敏性鼻炎、特应性皮炎、炎症性肠病、Crohn’s病、肝硬化、硬皮病或霍奇金淋巴瘤的疾病。

161.预防性治疗对IL-13活性相关疾病易感受试者的方法，包括：

确定所述受试者对IL-13活性相关疾病易感；

利用合理的药物设计选择能影响IL-13活性的物质；和

对受试者施用治疗有效量的所述物质。

162.权利要求161的方法，其中疾病为哮喘。

163.权利要求161或162中的任一项的方法，其中疾病为过敏性哮喘或非过敏性哮喘。

164.权利要求161的方法，其中疾病包括至少一种选自癌症、气道炎症、嗜酸性粒细胞增多症、纤维化、过量粘液产生、皮肤、胃肠道器官、血管或结缔组织炎症性疾病以及皮肤、胃肠道器官、血管或结缔组织自身免疫性疾病的疾病。

165.权利要求161的方法，其中疾病包括至少一种选自慢性阻塞性肺病、囊性纤维化、肺纤维化、过敏性鼻炎、特应性皮炎、炎症性肠病、Crohn’s病、肝硬化、硬皮病或霍奇金淋巴瘤的疾病。

166.权利要求161-165中的任一项的方法，其中所述物质通过在约2.0_距离内与SEQ ID NO：4氨基酸序列所定义的Glu49、Asn53、Gly69、Pro72、His73、Lys74和Arg86中的一个或多个氨基酸相互作用，而结合于IL-13。

167.根据权利要求64-97或129或130中的任一项而设计或选择的物质在制备预防或治疗与IL-13活性相关疾病的药物中的用途。

168.权利要求167的用途，其中所述物质能抑制IL-13活性。

169.权利要求167或168中任一项的用途，其中所述物质能抑制IL-13的体内活性。

170.权利要求167、168或169中任一项的用途，其中疾病为哮喘。

171.权利要求167-170中任一项的用途，其中疾病为过敏性哮喘或非过敏性哮喘。

172.权利要求167-170中任一项的用途，其中疾病包括至少一种选自癌症、气道炎症、嗜酸性粒细胞增多症、纤维化、过量粘液产生、皮肤、胃肠道器官、血管或结缔组织炎症性疾病以及皮肤、胃肠道器官、血管或结缔组织自身免疫性疾病的疾病。

173.权利要求167-170中任一项的用途，其中疾病包括至少一种选自慢性阻塞性肺病、囊性纤维化、肺纤维化、过敏性鼻炎、特应性皮炎、炎症性肠病、Crohn’s病、肝硬化、硬皮病或霍奇金淋巴瘤的疾病。

174.权利要求167-173中任一项的用途，其中所述物质通过在约2.0_距离内与SEQ ID NO：4氨基酸序列所定义的Glu49、Asn53、Gly69、Pro72、His73、Lys74和Arg86中的一个或多个氨基酸相互作用，而结合于IL-13。

175.根据权利要求65-105或129或130中的任一项而设计或选择的物质，在预防性或治疗与IL-13活性相关疾病中的用途。

176.权利要求175的用途，其中所述物质能抑制IL-13活性。

177.权利要求175或176的任一项的用途，其中所速物质能抑制IL-13的体内活性。

178.权利要求175、176或177任一项的用途，其中疾病为哮喘。

179.权利要求175-178中任一项的用途，其中疾病为过敏性哮喘或非过敏性哮喘。

180.权利要求175-177中任一项的用途，其中疾病包括至少一种选自癌症、气道炎症、嗜酸性粒细胞增多症、纤维化、过量粘液产生、皮肤、胃肠道器官、血管或结缔组织炎症性疾病以及皮肤、胃肠道器官、血管或结缔组织自身免疫性疾病的疾病。

181.权利要求175-177中任一项的用途，其中疾病包括至少一种选自慢性阻塞性肺病、囊性纤维化、肺纤维化、过敏性鼻炎、特应性皮炎、炎症性肠病、Crohn’s病、肝硬化、硬皮病或霍奇金淋巴瘤的疾病。

182.权利要求175-181中的任一项的用途，其中所述物质通过在约2.0_距离内与SEQ ID NO：4氨基酸序列所定义的Glu49、Asn53、Gly69、Pro72、His73、Lys74和Arg86中的一个或多个氨基酸相互作用，而结合于IL-13。