A conserved epitope III on hepatitis C virus E2 protein has alternate conformations facilitating cell binding or virus neutralization.
A conserved epitope III on hepatitis C virus E2 protein has alternate conformations facilitating cell binding or virus neutralization.
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DOI：
10.1073/pnas.2104242118
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发表时间：
2021-07-13
影响因子：
11.1
通讯作者：
Zhang P
中科院分区：
文献类型：
--
作者：
Deng L;Hernandez N;Zhong L;Holcomb DD;Yan H;Virata ML;Tarafdar S;Xu Y;He Y;Struble E;Alter HJ;Zhang P
表位III是丙型肝炎病毒E2糖蛋白上的一个片段，与宿主受体CD81结合，是抗体阻断丙型肝炎病毒进入的关键靶点。通过求解与位点特异性中和抗体mAb1H8结合的表位III的原子结构，我们发现，通过移动其氨基酸的侧链，该表位可以采用两种不同的构象，使其能够与mAb1H8或CD81结合。表位III不同构象状态的共存提示其可能在抗体反应的调节中发挥作用。这些发现应该有助于设计控制丙型肝炎病毒感染的策略，使平衡向有利于抗体识别而不是CD81结合的表位III构象倾斜。表位III是丙型肝炎病毒E2糖蛋白上524APTYSW529的高度保守的氨基酸基序，位于与宿主受体CD81结合的关键环路中，是阻断丙型肝炎病毒感染的最重要的抗体靶点之一。在这里，我们已经测定了表位III的X射线晶体结构，当它被位点特异性中和抗体1H8(MAb1H8)捕获时，分辨率为2.0。该复合体的快照显示，当限制在mAb1H8的结合槽中时，表位III具有相对刚性的结构，这赋予了表位两端的残基专一性。如此高的形状互补性让人想起“锁和钥匙”的作用模式，这种模式因结合的抗体与带有特定突变的表位不相容而得到加强。通过巧妙地将侧链定位在Tyr527、Ser528和Trp529的三个残基上，同时保持其余残基的空间刚性，该共晶复合体中的表位III采用了不同于先前描述的E2结构的独特构象。随着对分子对接和基于噬菌体展示的多肽相互作用的进一步分析，我们认识到是表位III中两组不同残基的排列产生了这些离散构象，使表位能够选择性地与mAb1H8或CD81相互作用。因此，这些观察结果提出了这样一种可能性，即局部表位III的构象动力学结合序列变化，可能作为一种调节机制来协调“mAb1H8样”抗体介导的免疫防御与CD81启动的丙型肝炎病毒感染。
Epitope III, a segment on the E2 glycoprotein of the hepatitis C virus (HCV) which binds to the host receptor CD81, is a key target for antibodies to block HCV entry. By solving the atomic structure of epitope III bound to a site-specific neutralizing antibody, mAb1H8, we showed that the epitope can adopt two distinct conformations by moving the side chains of its amino acids, allowing it to bind with either mAb1H8 or CD81. The coexistence of different conformational states of epitope III suggests its possible role in the regulation of antibody responses. These findings should help to design strategies to control HCV infection by tipping the balance toward epitope III conformations that favor antibody recognition rather than CD81 binding. Epitope III, a highly conserved amino acid motif of 524APTYSW529 on the hepatitis C virus (HCV) E2 glycoprotein, resides in the critical loop that binds to the host receptor CD81, thus making it one of the most important antibody targets for blocking HCV infections. Here, we have determined the X-ray crystal structure of epitope III at a 2.0-Å resolution when it was captured by a site-specific neutralizing antibody, monoclonal antibody 1H8 (mAb1H8). The snapshot of this complex revealed that epitope III has a relatively rigid structure when confined in the binding grooves of mAb1H8, which confers the residue specificity at both ends of the epitope. Such a high shape complementarity is reminiscent of the “lock and key” mode of action, which is reinforced by the incompatibility of an antibody binding with an epitope bearing specific mutations. By subtly positioning the side chains on the three residues of Tyr527, Ser528, and Trp529 while preserving the spatial rigidity of the rest, epitope III in this cocrystal complex adopts a unique conformation that is different from previously described E2 structures. With further analyses of molecular docking and phage display–based peptide interactions, we recognized that it is the arrangements of two separate sets of residues within epitope III that create these discrete conformations for the epitope to interact selectively with either mAb1H8 or CD81. These observations thus raise the possibility that local epitope III conformational dynamics, in conjunction with sequence variations, may act as a regulatory mechanism to coordinate “mAb1H8-like” antibody-mediated immune defenses with CD81-initiated HCV infections.
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影响因子：
7.7
作者：
Flyak, Andrew, I;Ruiz, Stormy E.;Bjorkman, Pamela J.
通讯作者：
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Biopython：用于计算分子生物学和生物信息学的免费 Python 工具。
DOI：
10.1093/bioinformatics/btp163
发表时间：
2009-06-01
期刊：
Bioinformatics (Oxford, England)
影响因子：
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作者：
Cock PJ;Antao T;Chang JT;Chapman BA;Cox CJ;Dalke A;Friedberg I;Hamelryck T;Kauff F;Wilczynski B;de Hoon MJ
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影响因子：
3.7
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DOI：
10.1073/pnas.1609780113
发表时间：
2016-11-08
影响因子：
11.1
作者：
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通讯作者：
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