Structure/Function Relationships in HIV-1 Co-Receptors

描述（由申请人提供）：本申请是为 标题为"结构/功能关系"的ROl A143847的竞争性更新 HIV-1共受体"Gp120与CD4受体的结合驱动了 gp120核心结构，并在其上产生/暴露共受体结合位点， gpl20。CCR5和CXCR4是生物学上最相关的HIV-1共受体。 在过去两年半的时间里，A143847号赠款支持了一些 这些研究使我的实验室能够绘制CCR5和CXCR4的决定因素， 辅助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 gp120和对于HIV-1融合和进入是必不可少的。我们还证明 CXCR4共受体功能依赖于Nt中的类似残基， 第二胞外环。我们对CCR5共受体抑制剂的研究 功能表明，不直接参与gp120结合的区域也发挥作用。 在病毒进入中起重要作用。这些发现成功地解决了 最初的具体目标，并奠定了基础，深入研究 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 融合共受体。为此，我们将阐明磺基酪氨酸的作用， 在CCR5和CXCR4介导融合和进入中，研究共受体相互作用 与来自非进化枝B分离物的包膜糖蛋白，并表征新的 通过干扰CCR5或CXCR4抑制病毒进入的先导化合物 辅助受体功能我们的工作将提供一个详细的分子图片， 介导HIV-1膜融合和病毒进入的蛋白质复合物， 促进开发更有效和更特异的抑制剂， 临床相关。

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.