Key mutations stabilize antigen-binding conformation during affinity maturation of a broadly neutralizing influenza antibody lineage.
Key mutations stabilize antigen-binding conformation during affinity maturation of a broadly neutralizing influenza antibody lineage.
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DOI：
10.1002/prot.24745
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发表时间：
2015-04
影响因子：
2.9
通讯作者：
Shaw, David E.
中科院分区：
文献类型：
--
作者：
Xu, Huafeng;Schmidt, Aaron G.;O'Donnell, Timothy;Therkelsen, Matthew D.;Kepler, Thomas B.;Moody, M. Anthony;Haynes, Barton F.;Liao, Hua-Xin;Harrison, Stephen C.;Shaw, David E.
关键词：
亲和力成熟是体细胞超突变和阳性选择产生对抗原具有增加亲和力的抗体的过程，在获得性体液免疫中是关键的。我们已经研究了人类B细胞谱系中亲和力获得的机制，其中两个主要的成熟途径，从一个共同的祖先，导致三个成熟的抗体，中和广泛的H1流感病毒。先前的工作表明，成熟抗体中增加的亲和力主要来源于抗原结合构象中CDR H3环的稳定化。我们现在已经使用分子动力学模拟和现有的晶体结构来识别潜在的关键成熟突变，并且我们已经分别使用进一步的模拟和实验亲和力测量来表征它们对CDR H3环和抗原结合的影响。在两种成熟途径中，轻链和重链之间的不同接触使CDR H3环稳定。每个通路中少至两个单位点突变可以赋予实质性的环稳定性，但它们中没有一个赋予其自身的实验可检测的稳定性。我们的研究结果支持模型的germinal中心的反应，其中两个或两个以上的突变可以发生没有伴随的选择，并显示不同的途径产生功能等效的抗体。Proteins 2014; 83：771-780.© 2014作者。蛋白质：结构，功能和生物信息学出版的威利期刊，公司。
Affinity maturation, the process in which somatic hypermutation and positive selection generate antibodies with increasing affinity for an antigen, is pivotal in acquired humoral immunity. We have studied the mechanism of affinity gain in a human B-cell lineage in which two main maturation pathways, diverging from a common ancestor, lead to three mature antibodies that neutralize a broad range of H1 influenza viruses. Previous work showed that increased affinity in the mature antibodies derives primarily from stabilization of the CDR H3 loop in the antigen-binding conformation. We have now used molecular dynamics simulations and existing crystal structures to identify potentially key maturation mutations, and we have characterized their effects on the CDR H3 loop and on antigen binding using further simulations and experimental affinity measurements, respectively. In the two maturation pathways, different contacts between light and heavy chains stabilize the CDR H3 loop. As few as two single-site mutations in each pathway can confer substantial loop stability, but none of them confers experimentally detectable stability on its own. Our results support models of the germinal center reaction in which two or more mutations can occur without concomitant selection and show how divergent pathways have yielded functionally equivalent antibodies. Proteins 2014; 83:771–780. © 2014 The Authors. Proteins: Structure, Function, and Bioinformatics Published by Wiley Periodicals, Inc.
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影响因子：
5.3
作者：
Kortkhonjia E;Brandman R;Zhou JZ;Voelz VA;Chorny I;Kabakoff B;Patapoff TW;Dill KA;Swartz TE
通讯作者：
Swartz TE
影响因子：
46.9
作者：
通讯作者：
--
DOI：
10.1038/nsb930
发表时间：
2003-06-01
期刊：
NATURE STRUCTURAL BIOLOGY
影响因子：
--
作者：
Li, YL;Li, HM;Mariuzza, RA
通讯作者：
Mariuzza, RA
影响因子：
5.8
作者：
Volpe, JM;Cowell, LG;Kepler, TB
通讯作者：
Kepler, TB
影响因子：
2
作者：
KEPLER, TB;PERELSON, AS
通讯作者：
PERELSON, AS