Structure/Function Relationships in HIV-1 Co-Receptors

描述(由申请人提供)：本申请表适用于 竞争性续签《结构/功能关系》A143847 在HIV-1共受体中。gp120与CD4受体结合推动 Gpl2O的核心结构，并在上创建/暴露共受体结合位点 Gpl2O.CCR5和CXCR4是最具生物学意义的HIV-1共受体。 在过去的两年半里，赠款A143847支持了许多 使我的实验室能够绘制CCR5和CXCR4决定因素的研究 共受体功能。我们证明了带负电荷的残基和 CCR5氨基末端结构域(NT)中的磺基酪氨酸直接与 Gpl2O是HIV-1融合和进入所必需的。我们还演示了 CXCR4共同受体的功能依赖于NT和 第二个细胞外循环。CCR5辅受体抑制剂的研究 功能表明，没有直接参与gpl20结合的区域也发挥作用 在病毒入侵中扮演着重要的角色。这些发现成功地解决了 最初的具体目标，为深入研究奠定了基础 共受体结构/功能关系。 我们的持续目标是确定HIV-1包膜糖蛋白如何与 融合辅助受体。为此，我们将阐明磺基酪氨酸的作用 在CCR5和CXCR4介导的融合和进入中，研究共同受体的相互作用 与来自非B分支分离株的包膜糖蛋白分离，并鉴定了新的 通过干扰CCR5或CXCR4抑制病毒侵入的先导化合物 共受体功能。我们的工作将提供一幅详细的分子图像 介导HIV-1膜融合和病毒进入的蛋白质复合体，并将 推动更有效和更特异的抑制剂的开发 临床上相关的。

DESCRIPTION (Provided by the applicant): This application is for the competitive renewal of ROl A143847 entitled "Structure/function relationships in HIV-1 co-receptors." Gp120 binding to the CD4 receptor drives reordering of the gpl2O core structure and creates/exposes a co-receptor binding site on gpl2O. CCR5 and CXCR4 are the most biologically relevant HIV-1 co-receptors. Over the past two and a half years, grant A143847 has supported a number of studies that enabled my laboratory to map the determinants of CCR5 and CXCR4 co-receptor function. We demonstrated that negatively charged residues and sulfotyrosines in the CCR5 amino-terminal domain (Nt) interact directly with gpl2O and are indispensable for HIV-1 fusion and entry. We also demonstrated that CXCR4 co-receptor function depends on similar residues in the Nt and second extracellular loop. Our studies with inhibitors of CCR5 co-receptor function showed that regions not directly involved in gpl20 binding also play an important role in viral entry. These findings successfully address the original specific aims and lay the groundwork for advanced studies of co-receptor structure/function relationships. Our continuing goal is to define how HIV-1 envelope glycoproteins interact with fusion co-receptors. To this end, we will elucidate the role of sulfotyrosines in CCR5- and CXCR4-mediated fusion and entry, study co-receptor interactions with envelope glycoproteins from non-clade B isolates, and characterize novel lead compounds that inhibit viral entry by interfering with CCR5 or CXCR4 co-receptor function. Our work will provide a detailed molecular picture of the protein complex that mediates HIV-1 membrane fusion and viral entry, and will advance the development of more potent and specific inhibitors that are clinically relevant.