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首页> 外文期刊>Journal of Molecular Biology >Structure of Hepatitis C Virus Envelope Glycoprotein E1 Antigenic Site 314-324 in Complex with Antibody IGH526
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Structure of Hepatitis C Virus Envelope Glycoprotein E1 Antigenic Site 314-324 in Complex with Antibody IGH526

机译：与抗体IGH526结合的丙型肝炎病毒包膜糖蛋白E1抗原位点314-324的结构

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摘要

Hepatitis C virus (HCV) is a positive-strand RNA virus within the Flaviviridae family. The viral "spike" of HCV is formed by two envelope glycoproteins, E1 and E2, which together mediate viral entry by engaging host receptors and undergoing conformational changes to facilitate membrane fusion. While E2 can be readily produced in the absence of E1, E1 cannot be expressed without E2 and few reagents, including monoclonal antibodies (mAbs), are available for study of this essential HCV glycoprotein. A human mAb to E1, IGH526, was previously reported to cross-neutralize different HCV isolates, and therefore, we sought to further characterize the IGH526 neutralizing epitope to obtain information for vaccine design. We found that mAb IGH526 bound to a discontinuous epitope, but with a major component corresponding to El residues 314-324. The crystal structure of IGH526 Fab with this E1 glycopeptide at 1.75 angstrom resolution revealed that the antibody binds to one face of an alpha-helical peptide. Single mutations on the helix substantially lowered IGH526 binding but did not affect neutralization, indicating either that multiple mutations are required or that additional regions are recognized by the antibody in the context of the membrane-associated envelope oligomer. Molecular dynamics simulations indicate that the free peptide is flexible in solution, suggesting that it requires stabilization for use as a candidate vaccine immunogen. (C) 2015 Elsevier Ltd. All rights reserved.
机译：丙型肝炎病毒（HCV）是黄病毒科中的一种正链RNA病毒。 HCV的病毒“尖峰”由两个包膜糖蛋白E1和E2形成，它们通过与宿主受体结合并经历构象变化以促进膜融合而共同介导病毒进入。尽管在没有E1的情况下可以很容易地产生E2，但是如果没有E2则无法表达E1，并且很少有试剂（包括单克隆抗体（mAb））可用于研究这种基本的HCV糖蛋白。先前报道了针对E1的人mAb IGH526可交叉中和不同的HCV分离物，因此，我们试图进一步表征IGH526中和表位，以获得疫苗设计信息。我们发现mAb IGH526结合到不连续的表位，但是具有对应于E1残基314-324的主要成分。具有这种E1糖肽且分辨率为1.75埃的IGH526 Fab的晶体结构表明，该抗体与α-螺旋肽的一个表面结合。螺旋上的单个突变大大降低了IGH526的结合力，但不影响中和作用，表明在膜相关的包膜低聚物的背景下，要么需要多个突变，要么抗体可以识别其他区域。分子动力学模拟表明游离肽在溶液中具有柔性，表明其需要稳定才能用作候选疫苗免疫原。 （C）2015 Elsevier Ltd.保留所有权利。

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