Structure of the core ectodomain of the hepatitis C virus envelope glycoprotein 2.
Structure of the core ectodomain of the hepatitis C virus envelope glycoprotein 2.
复制标题
DOI：
10.1038/nature13117
复制
发表时间：
2014-05-15
期刊：
影响因子：
64.8
通讯作者：
Marcotrigiano, Joseph
中科院分区：
文献类型：
--
作者：
Khan, Abdul Ghafoor;Whidby, Jillian;Miller, Matthew T.;Scarborough, Hannah;Zatorski, Alexandra V.;Cygan, Alicja;Price, Aryn A.;Yost, Samantha A.;Bohannon, Caitlin D.;Jacob, Joshy;Grakoui, Arash;Marcotrigiano, Joseph
丙型肝炎病毒（HCV）是一个重大的公共卫生问题，全球约有1.6亿人感染。HCV感染常导致慢性肝炎、肝硬化和肝细胞癌。目前尚无疫苗，现有的治疗方法对某些基因型有效，但并非对所有基因型都有效。HCV是一种有包膜的病毒，具有两种表面糖蛋白（E1和E2）。E2通过与B类I型清道夫受体（SR - BI）和CD81相互作用与宿主细胞结合，并作为中和抗体的靶点。尽管预测E2是一种II类病毒融合蛋白，但对于介导细胞进入和膜融合的分子机制知之甚少。在此我们描述了分辨率为2.4 Å的与一个Fab复合的E2核心结构域的结构。E2核心具有紧凑的球状结构域结构，主要由β链和无规卷曲以及两个小的α螺旋组成。这些链排列成两个垂直的片层（A和B），它们通过一个广泛的疏水核心和二硫键结合在一起。片层A具有一种在病毒和细胞蛋白中常见的IgG样折叠，而片层B代表一种新的折叠。基于溶液的研究表明，全长E2胞外结构域具有类似的球状结构，并且在暴露于低pH时不会发生显著的构象或寡聚体重排。因此，IgG样折叠是E2与II类膜融合蛋白唯一的共同特征。这些结果为HCV进入细胞提供了前所未有的见解，并将有助于开发HCV疫苗和新的抑制剂。
Hepatitis C virus (HCV) is a significant public health concern with approximately 160 million people infected worldwide . HCV infection often results in chronic hepatitis, liver cirrhosis, and hepatocellular carcinoma. No vaccine is available and current therapies are effective against certain, but not all, genotypes. HCV is an enveloped virus with two surface glycoproteins (E1 and E2). E2 binds to the host cell through interactions with scavenger receptor class B type I (SR-BI) and CD81, and serves as a target for neutralizing antibodies . Little is known about the molecular mechanism that mediates cell entry and membrane fusion, although E2 is predicted to be a class II viral fusion protein. Here we describe the structure of the E2 core domain in complex with an Fab at 2.4 Å resolution. The E2 core has a compact, globular domain structure, consisting mostly of beta strands and random coil with two small alpha helices. The strands are arranged in two, perpendicular sheets (A and B), which are held together by an extensive hydrophobic core and disulfide bonds. Sheet A has an IgG-like fold that is commonly found in viral and cellular proteins while sheet B represents a novel fold. Solution-based studies demonstrate that the full-length E2 ectodomain has a similar globular architecture and does not undergo significant conformational or oligomeric rearrangements upon exposure to low pH. Thus, the IgG-like fold is the only feature that E2 shares with class II membrane fusion proteins. These results provide unprecedented insights into HCV entry and will assist in developing an HCV vaccine and new inhibitors.
登录
查看更多内容
影响因子：
6.7
作者：
Krey T;d'Alayer J;Kikuti CM;Saulnier A;Damier-Piolle L;Petitpas I;Johansson DX;Tawar RG;Baron B;Robert B;England P;Persson MA;Martin A;Rey FA
通讯作者：
Rey FA
影响因子：
4.8
作者：
Drummer, HE;Poumbourios, P
通讯作者：
Poumbourios, P
影响因子：
6.1
作者：
Kozin, MB;Svergun, DI
通讯作者：
Svergun, DI
DOI：
10.1107/s0907444909052925
发表时间：
2010-02
期刊：
Acta crystallographica. Section D, Biological crystallography
影响因子：
--
作者：
Adams PD;Afonine PV;Bunkóczi G;Chen VB;Davis IW;Echols N;Headd JJ;Hung LW;Kapral GJ;Grosse-Kunstleve RW;McCoy AJ;Moriarty NW;Oeffner R;Read RJ;Richardson DC;Richardson JS;Terwilliger TC;Zwart PH
通讯作者：
Zwart PH
DOI：
10.1126/science.1243876
发表时间：
2013-11-29
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Kong L;Giang E;Nieusma T;Kadam RU;Cogburn KE;Hua Y;Dai X;Stanfield RL;Burton DR;Ward AB;Wilson IA;Law M
通讯作者：
Law M