MINIPROTEIN MIMETICS

该项目的中心目标是使用微型蛋白模拟物 加上gp120/cd4复合体的新结构， 设计人类细胞与HIV-1相互作用的拮抗剂， 导致艾滋病的人类免疫缺陷病毒。T细胞 HIV-1的对接和进入，是中国细胞感染的主要途径 艾滋病是由T细胞表面的特定识别所驱动的 由HIV包膜蛋白gp120编码的CD4蛋白。这个 CD4的晶体结构是已知的，其晶体结构 与gp120结合的复合体近在咫尺。中的结构构件 已经确定了这两个蛋白质伙伴，它们被提议 在识别CD4-gp120中起关键作用。前进中的高点 对蛋白质参与蛋白结构的理解 病毒细胞识别与先进的技术 模仿设计现在使将结构组合成为可能 测定、建模和微型蛋白质工程以获得 对结构基础的高级力学理解 CD4-gp120相互作用和设计新的艾滋病拮抗剂。 本项目的具体目标是：(1)获得微小蛋白 移植CD4和gp120结合位点的构建 组成构象受限的小蛋白 化学和重组DNA方法制备支架材料 并建立它们的CD4/gp120拮抗剂活性；(2)构建 噬菌体展示的CD4和gp120模拟微蛋白文库 并用它们来鉴定新的c4和gp120结合拮抗剂。 以及检查所需的关键结构元素 Cd4/gp120拮抗剂设计；(3)确定高分辨率 与CD_4或CD_4复合的关键微蛋白结构 Gp120，并使用这些复合体中的结合界面结构 为了完善CD-4中关键结构元素的拓扑图- Gp120识别。总体而言，该项目将生产微型蛋白质 两种免疫识别受体的模拟结构 (Cd4)和逆转录病毒包膜糖蛋白(Gp120)； 先进的机械定义的关键结构元素 Cd4-gp120相互作用；以及小型企业的结构铅信息 分子拮抗剂设计。从长远来看，模仿策略 推导出的结果将有助于机构的确定和设计 其他蛋白质-蛋白质相互作用的拮抗剂 艾滋病，如gp41-gp120和趋化因子受体 与人类细胞-HIV-1相关的相互作用 对接和病毒入侵。

The central objective of this Project is to use miniprotein mimetic together with the emerging structure of the gp120/CD4 complex to design antagonists of the interaction of human cells with HIV-1, the human immunodeficiency virus responsible for AIDS. T-cell docking and entry by HIV-1, a major route of cell infection in AIDS, is driven by specific recognition of the T-cell surface protein CD4 by the HIV envelope protein gp120. The crystallographic structure of CD4 is known, and that of its complex with gp120 is close at hand. Structural components in both protein partners have been identified which are proposed to play key roles in CD4-gp120 recognition. The advancing high resolution structural understanding of the protein participants in virus-cell recognition together with the advancing technology of mimetics design now make it possible to combine structure determination, modeling and miniprotein engineering to obtain an advanced mechanistic understanding of the structural basis of CD4-gp120 interaction and to design new antagonists for AIDS. The specific aims of this Project are: (1) obtain miniprotein constructions by transplanting CD4 and gp120 binding site components into conformationally constrained miniprotein presentation scaffolds by chemical and recombinant DNA methods and establish their CD4/gp120 antagonist activities; (2) construct phage displayed libraries of CD4- and gp120-mimetic miniproteins and use these to identify novel CD4 and gp120 binding antagonists as well as to examine the key structural elements needed for CD4/gp120 antagonist design; (3) determine the high resolution structures of key miniprotein constructs complexed with CD4 or gp120 and use the binding interface structures in these complexes to refine the topological map of key structural elements in CD4- gp120 recognition. Overall, this project will yield miniprotein mimetic constructions for both an immunorecognition receptor (CD4) and a retroviral envelope glycoprotein (gp120);and advanced mechanistic definition of key structural elements for CD4-gp120 interaction; and structural lead information for small molecule antagonist design. Long term, the mimetics strategies derived will be useful to determine mechanism of, and design antagonists for other protein-protein interactions important in AIDS, such as the gp41-gp120 and chemokine receptor interactions, that also are associated with human cell - HIV-1 docking and viral entry.