Crystallographic studies of HIV-1 Vif Function

描述（由申请人提供）：人类免疫缺陷病毒（HIV）导致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。尽管有几种抗艾滋病毒药物，但艾滋病仍然无法治愈。这一建议旨在揭示病毒感染因子（Vif）功能的结构机制，Vif是HIV-1病毒在体内复制所必需的辅助蛋白。这些研究将有助于确定开发Vif抑制化合物的潜在靶点，这可能会导致新的抗hiv药物。通过劫持宿主细胞的Cul5-ElonginB-ElonginC泛素连接酶机制，Vif能够加速APOBEC3G的泛素化，APOBEC3G是人类先天免疫系统为阻断病毒生命周期而产生的胞苷脱氨酶。通过泛素化APOBEC3G， Vif将宿主酶靶向到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进行特异性相互作用，因此Vif代表了一种具有多种治疗干扰机会的新型药物靶点。在本课题中，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 - elongc -拉长b的三元配合物结构，(2)cul5 - vif -拉长c -拉长b的四元配合物结构，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，由人类免疫缺陷病毒（HIV）感染引起。虽然有几类抗艾滋病药物可用，但没有一种能治愈艾滋病。这一建议旨在研究一个关键的HIV蛋白功能的结构基础，以帮助未来设计新的抗HIV药物。

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.