MINIPROTEIN MIMETICS

本项目的中心目标是利用微蛋白模拟物 与gp 120/CD 4复合物的新结构一起， 设计人类细胞与HIV-1相互作用的拮抗剂， 导致艾滋病的人体免疫缺陷病毒。 t细胞 HIV-1的对接和进入，这是细胞感染的主要途径， 艾滋病，是由T细胞表面的特异性识别驱动的 HIV包膜蛋白gp 120对CD 4蛋白的作用。的 CD 4的晶体结构是已知的， 与GP 120的复合体近在咫尺。 中的结构部件 已经鉴定了两种蛋白质伴侣， 在CD 4-gp 120识别中起关键作用。 前进的高 蛋白质参与者的分辨率结构理解 病毒细胞识别以及先进的 模仿设计现在使联合收割机结构 测定、建模和微蛋白工程，以获得 先进的机械理解的结构基础， CD 4-gp 120相互作用，并设计新的艾滋病拮抗剂。 本项目的具体目标是：（1）获得微蛋白 通过移植CD 4和gp 120结合位点的构建体 构象受限的小蛋白 通过化学和重组DNA方法的呈递支架 并建立其CD 4/gp 120拮抗活性;（2）构建 噬菌体展示的CD 4-和gp 120-模拟小蛋白文库 并使用这些来鉴定新的CD 4和gp 120结合拮抗剂 以及审查所需的关键结构要素， CD 4/gp 120拮抗剂设计;（3）高分辨率测定 与CD 4复合的关键微蛋白结构，或 gp 120并在这些复合物中使用结合界面结构 以完善CD 4 - 3中关键结构元件的拓扑图， gp 120识别 总的来说，这个项目将产生微蛋白 免疫识别受体的模拟结构 (CD4)和逆转录病毒包膜糖蛋白（gp 120）;和 关键结构元素的高级机械定义， CD 4-gp 120相互作用;以及小细胞肺癌的结构性先导信息 分子拮抗剂设计。 从长远来看，模仿策略 将有助于确定机制，设计 其他蛋白质-蛋白质相互作用的拮抗剂， 艾滋病，如gp 41-gp 120和趋化因子受体 相互作用，这也与人类细胞-艾滋病毒-1 对接和病毒进入。

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.