Structure and function of Hepacivirus envelope glycoprotein

 描述(申请人提供)：丙型肝炎病毒(丙型肝炎病毒)慢性感染全球人口的2-3%，使患者易患慢性肝病和肝癌。为了对抗这一重大的公共卫生威胁，对病毒分子的详细了解将极大地促进疫苗和抗病毒药物的设计。丙型肝炎病毒包膜糖蛋白(Env)是由病毒E1和E2糖蛋白的异源二聚体组成，对病毒附着和进入宿主细胞以及感染病毒颗粒的组装具有重要作用。E1和E2糖蛋白是药物和免疫干预的潜在靶点。这项应用的目的是确定丙型肝炎病毒包膜糖蛋白的高分辨率晶体结构，以及在氨基酸水平上糖蛋白的功能。结果将有助于 合理设计抗病毒药物和疫苗，了解病毒进入机制。具体目的是(1)确定丙型肝炎病毒E2和E2受体复合体的高分辨晶体结构；(2)用鸟枪法研究单个氨基酸残基在蛋白质功能中的作用；(3)确定丙型肝炎病毒E1和E1E2复合体的高分辨晶体结构。

 DESCRIPTION (provided by applicant): Hepatitis C virus (HCV) chronically infects 2-3% of the global population, predisposing the patients to chronic liver diseases and liver cancer. To combat this major public health threat, a detailed understanding of the viral molecules will greatly facilitate vaccine and anti-viral drug design. The HCV envelope glycoproteins (Env), comprised of heterodimers of the E1 and E2 viral glycoproteins, are important for viral attachment and entry into host cells, and the assembly of infectious virus particles. The E1 and E2 glycoproteins are potential targets for pharmacological and immunological intervention. The goals of this application are to determine the high-resolution crystal structure of HCV envelope glycoproteins, and the functions of the glycoproteins at the amino acid level. The results will aid the rational design of anti-viral drugs and vaccines, and to understand the viral entry mechanism. The specific aims are (i) to determine the high-resolution crystal structure of HCV E2 and E2:receptor complex; (ii) to study the roles of individual amino acid residues in protein functions by a shotgun mutagenesis approach; and (iii) to determine the high-resolution crystal structures of HCV E1 and E1E2 complex.