PROTEIN DISSECTION OF THE ENVELOPE (GP120/GP41) OF HIV

（改编自应用程序）广泛的，长期的目标， 这里提出的研究是为了增加关于结构/功能的知识 HIV包膜糖蛋白复合物（gp 120/gp 41）的关系。在 尽管作出了相当大的努力，但迄今仍未能取得 GP 120、GP 41或GP 120/GP 41复合物的详细结构。认识 这段历史，解决这个问题的新方法，利用蛋白质解剖， 结合噬菌体展示和组合化学， 建议的研究。 拟议研究的三个具体目标是： 1.为了确定高分辨率的X射线晶体结构， HIV gp 41的三聚体核心。 2.为了鉴定gp 120/gp 41复合物的稳定折叠亚片段， 蛋白质解剖，获得这些衍射质量的晶体 亚片段，并通过X射线解析这些亚片段的结构 晶体学方法 3.为了鉴定使gp 120的结构刚性化的配体，使用这些 配体，以获得GP 120的衍射质量晶体，并解决 这些配体-gp 120复合物的结构通过X射线晶体学 方法. 4.鉴定HIV感染的D肽抑制剂，并表征 这些抑制剂的结构与GP 41的片段结合。 HIV的包膜糖蛋白（Env gp）是病毒粒子所必需的 附着到细胞上，随后病毒和细胞融合， 膜。因此，包膜对于细胞的感染至关重要， 艾滋病。此外，基本上所有的中和抗体活性在 HIV-1感染的宿主直接针对Env gp。由于这些和其他 确定gp 120-gp 41复合物的结构，以及 其组成部分，一直是努力开发新的 治疗艾滋病的方法。尽管有很多努力，但高... 缺乏关于Enz gp的解析结构信息。本 该提案旨在通过新的方法获得这一信息。 这项研究旨在促进我们对 HIV包膜的结构/功能关系， 促进用于治疗艾滋病的基于结构的药物设计。

(Adapted from the application) The broad, long-term objective of the research proposed here is to increase knowledge about structure/function relationships for the HIV envelope glycoprotein complex (gp120/gp41). In spite of considerable efforts, it has not yet been possible to obtain a detailed structure for gp120, gp41 or the gp120/gp41 complex. Recognizing this history, new approaches to the problem, utilizing protein dissection, coupled with phage display and combinatorial chemistry, will be applied in the proposed research. The three specific aims of the proposed research are: 1. To determine the high resolution X-ray crystal structure of the trimeric core of HIV gp41. 2. To identify stable, folded subfragments of the gp120/gp41 complex by protein dissection, obtain diffraction-quality crystals of these subfragments, and solve the structures of these subfragments by X-ray crystallographic methods. 3. To identify ligands that rigidify the structure of gp120, use these ligands to obtain diffraction-quality crystals of gp120 and solve the structures of these ligand-gp120 complexes by X-ray crystallographic methods. 4. To identify D-peptide inhibitors of HIV infection, and characterize the structures of these inhibitors bound to fragments of gp41. The envelope glycoprotein (Env gp) of HIV is required for virion attachment to cells and subsequent fusion of the viral and cellular membranes. The envelope is therefore crucial for infection of cells by HIV. In addition, essentially all of the neutralizing antibody activity in HIV-1 infected hosts is directed against Env gp. For these and other reasons, determining the structure of the gp120-gp41 complex, and components thereof, has been a major goal of efforts to develop new approaches for the treatment of AIDS. In spite of numerous efforts, high- resolution structural information about Enz gp is lacking. The present proposal is aimed at obtaining this information through new approaches. This research is designed to advance our understanding of structure/function relationships of the HIV envelope, ultimately facilitating structure-based drug design for the treatment of AIDS.