STRUCTURAL STUDIES OF HIV VIF AND ITS CELLULAR BINDING PARTNERS

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 人类抗病毒蛋白APOBEC 3G诱导广泛的突变，并阻止HIV DNA的积累，使病毒不具有感染性。为了逃避这种宿主防御机制，HIV表达病毒体感染因子（Vif）。 Vif模拟多组分细胞泛素连接酶中的底物受体，并募集连接酶以聚泛素化APOBEC 3G用于蛋白酶体介导的降解。通过与APOBEC 3G和泛素连接酶组分ElonginB/ElonginC和Cullin 5的直接相互作用，Vif使HIV能够逃避先天免疫反应的关键因素。 我们的总体目标是建立HIV Vif隔离APOBEC 3G的结构原理，并提供Vif与宿主细胞蛋白之间相互作用的结构细节。我们将确定HIV Vif与其各种细胞结合伴侣的复合物以及Vif/APOBEC 3G/泛素连接酶的完整复合物的晶体结构。具体来说，我们将研究含有i）Vif-ElonginB/ElonginC，ii）Vif-Cullin 5和iii）Vif-APOBEC 3G相互作用的复合物的结构。从这些研究中获得的结构信息将提供对HIV Vif劫持宿主泛素连接酶以规避APOBEC 3G的先天免疫应答的机制的深入理解。此外，这些结构细节将使Vif抑制剂的合理设计成为可能，从而为HIV感染提供新的治疗干预措施。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Human antiviral protein APOBEC3G induces extensive mutations and prevents the accumulation of HIV DNA rendering the virus non-infectious. To evade this host defense mechanism, HIV expresses the virion infectivity factor (Vif). Vif mimics the substrate receptor in a multi-component cellular ubiquitin ligase and recruits the ligase to polyubiquitinate APOBEC3G for proteasome-mediated degradation. Through direct interactions with APOBEC3G and the ubiquitin ligase components ElonginB/ElonginC and Cullin5, Vif enables HIV to escape a key element of the innate immune response. Our overall goal is to establish the structural principles by which HIV Vif sequesters APOBEC3G and to provide structural details of the interactions between Vif and host cellular proteins. We will determine the crystal structures of HIV Vif in complex with its various cellular binding partners as well as a complete complex of Vif/APOBEC3G/ubiquitin ligase. Specifically, we will examine the structures of complexes that contain i) the Vif-ElonginB/ElonginC, ii) the Vif-Cullin5, and iii) the Vif-APOBEC3G interactions. Structural information gained from these studies will provide an in-depth understanding of the mechanism by which HIV Vif hijacks the host ubiquitin ligase to circumvent the innate immune response from APOBEC3G. Further, the structural details will enable the rational design of Vif inhibitors that might lead to new therapeutic interventions for HIV infection.