Crystallographic studies of HIV-1 Vif Function

HIV-1 Vif 功能的晶体学研究

基本信息

批准号：
7413656
负责人：
NING ZHENG
金额：
$ 18.7万
依托单位：
UNIVERSITY OF WASHINGTON
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-05-01 至 2009-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7413656
关键词：
Acquired Immunodeficiency Syndrome Affinity Alanine Anti-Retroviral Agents Baculoviruses Binding Biological Assay C-terminal Categories Cells Collaborations Complex Crystallization Crystallography Cytidine Deaminase Drug Delivery Systems Drug resistance Enzymes Future HIV HIV-1 Host Defense Hot Spot Human In Vitro Insecta Intervention Lead Length Life Cycle Stages Maps Methods Molecular N-terminal Natural Immunity Peptides Pharmaceutical Preparations Principal Investigator Process Proteins Recruitment Activity Research Resolution Scanning Site Solubility Structure System Testing Therapeutic Therapeutic Agents Toxic effect Ubiquitination Viral Viral Genome Viral Physiology Viral Proteins Virus Virus Diseases X-Ray Crystallography base cost design in vivo multicatalytic endopeptidase complex mutant novel novel therapeutics pandemic disease programs receptor research study scaffold ubiquitin ligase

项目摘要

DESCRIPTION (provided by applicant): The human immunodeficiency virus (HIV) causes the acquired immunodeficiency syndrome (AIDS), which is the deadliest pandemic of the modern world. Despite the availability of several categories of anti-HIV drugs, AIDS remains incurable. This proposal is aimed at revealing the structural mechanisms underlying the function of viral infectivity factor (Vif), an HIV-1 accessory protein essential for viral replication in vivo. The proposed studies will help identify the potential target sites for developing Vif- inhibiting compounds, which might lead to novel anti-HIV drugs. Upon hijacking the Cul5-ElonginB-ElonginC ubiquitin ligase machinery of the host cells, Vif is able to accelerate the ubiquitination of APOBEC3G, which is a cytidine deaminase produced by the human innate immunity system in order to block viral life cycle. By ubiquitinating APOBEC3G, Vif targets the host enzyme to the proteasome and induces its rapid degradation. Since specific interactions with at least three host proteins are required for its function, Vif represents a novel drug target with multiple opportunities for therapeutic interference. In this proposal, we plan to use protein complex X-ray crystallography to reveal the structural basis of Vif's function. Specifically, we propose to determine (1) the ternary complex structure of Vif-ElonginC-ElonginB, (2) the quaternary complex structure of Cul5-Vif-ElonginC-ElonginB, and (3) the structure mechanisms of Vif-APOBEC3G interactions. AIDS, the deadliest pandemic of the modern world, is caused by human immuno- deficiency virus (HIV) infection. Although several categories of anti-HIV drugs are available, none can cure AIDS. This proposal is aimed at studying the structural basis of the functions of a crucial HIV protein in order to help future design of novel anti-HIV drugs.

描述（由申请人提供）：人类免疫缺陷病毒（HIV）引起获得性免疫缺陷综合症（艾滋病），这是现代世界最致命的流行病。尽管有多种抗艾滋病毒药物可供使用，但艾滋病仍然无法治愈。该提案旨在揭示病毒感染因子（Vif）功能的结构机制，病毒感染因子是一种HIV-1辅助蛋白，对于体内病毒复制至关重要。拟议的研究将有助于确定开发 Vif 抑制化合物的潜在靶位点，这可能会产生新型抗 HIV 药物。在劫持宿主细胞的 Cul5-ElonginB-ElonginC 泛素连接酶机制后，Vif 能够加速 APOBEC3G 的泛素化，APOBEC3G 是人类先天免疫系统产生的胞苷脱氨酶，旨在阻断病毒生命周期。通过泛素化 APOBEC3G，Vif 将宿主酶靶向蛋白酶体并诱导其快速降解。由于其功能需要与至少三种宿主蛋白发生特异性相互作用，Vif 代表了一种具有多种治疗干扰机会的新型药物靶点。在这个提案中，我们计划利用蛋白质复合物X射线晶体学来揭示Vif功能的结构基础。具体来说，我们建议确定（1）Vif-ElonginC-ElonginB的三元复合物结构，（2）Cul5-Vif-ElonginC-ElonginB的四元复合物结构，以及（3）Vif-APOBEC3G相互作用的结构机制。艾滋病是现代世界最致命的流行病，是由人类免疫缺陷病毒（HIV）感染引起的。尽管有多种抗艾滋病毒药物可供使用，但没有一种药物可以治愈艾滋病。该提案旨在研究关键艾滋病毒蛋白功能的结构基础，以帮助未来新型抗艾滋病毒药物的设计。