NMR STUDIES OF THE HIV ENVELOPE PROTEINS

HIV 包膜蛋白的核磁共振研究

• 批准号: 6642143
• 负责人: Michael S. Caffrey
• 金额: $ 24.11万
• 依托单位: UNIVERSITY OF ILLINOIS AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-08-15 至 2005-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6642143
• 关键词: HIV envelope protein gp120; HIV envelope protein gp41; HIV infections; bioimaging /biomedical imaging; gene mutation; membrane fusion; nuclear magnetic resonance spectroscopy; protein structure function; site directed mutagenesis

gp4l plays a central role in HIV infection by initiating the fusion of the viral and target cell membranes, thereby allowing the viral core particle to enter the cytoplasm of the target cell. Therapies designed to disrupt gp4l function are especially attractive for the prevention and treatment of AIDS patients because of their potential prophylactic properties, as well as being alternative and complementary therapies to the protease and reverse transcriptase inhibitors currently employed. Recently, structural information has become available for regions of the gp4l and gp120 in isolation; however, there is no structural information for the gp41/gp120 complex. Furthermore, there are significant gaps in our knowledge concerning the molecular basis for gp41-mediated membrane fusion and the mechanism of peptide inhibition of gp4l function. The long term goal of this proposal is to relate the structural properties of gp4l to its functional properties, which could serve as the basis for the design of new therapies for the prevention and treatment of AIDS. The general hypotheses are that: (i) the loop region of the gp4l ectodomain interacts with the C1 and C5 domains of gp120 while gp4l is in a compact conformation; (ii) peptide inhibitors of HIV infection bind to the compact form of gp41. The specific aims are: 1) determination of the structure and dynamic properties of the HIV gp4l ectodomain; 2) elucidation of the mechanism of gp4l peptide inhibition of HIV infection; 3) development of a site-directed mutagenesis system to relate HIV gp4l structure to function. In this proposal, a combined approach of molecular biology, biochemistry and NMR spectroscopy will be employed.

GP4L通过启动病毒和靶细胞膜的融合在HIV感染中起着核心作用，从而允许病毒核心颗粒进入靶细胞的细胞质。 旨在破坏GP4L功能的疗法对于预防和治疗AIDS患者的潜在预防性特性特别有吸引力，并且是当前使用的蛋白酶和逆转录酶抑制剂的替代和互补疗法。 最近，孤立的GP4L和GP120区域已获得结构信息。但是，GP41/GP120复合物没有结构信息。 此外，关于GP41介导的膜融合的分子基础和肽抑制GP4L功能的机理，我们的知识存在很大的差距。 该提案的长期目标是将GP4L的结构特性与其功能特性联系起来，该特性可以作为设计预防和治疗艾滋病的新疗法的基础。 一般假设是：（i）GP4L外生域的环区域与GP120的C1和C5结构域相互作用，而GP4L处于紧凑的构象中； （ii）HIV感染的肽抑制剂与GP41的紧凑形式结合。 具体目的是：1）确定HIV GP4L外生域的结构和动态特性； 2）阐明GP4L肽抑制HIV感染的机理； 3）开发定向的诱变系统，以将HIV GP4L结构与功能相关联。 在此提案中，将采用分子生物学，生物化学和NMR光谱法的综合方法。