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

HIV 包膜 (GP120/GP41) 的蛋白质解剖

• 批准号: 6336553
• 负责人: PETER S KIM
• 金额: $ 22.2万
• 依托单位: WHITEHEAD INSTITUTE FOR BIOMEDICAL RES
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-08-01 至 2001-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6336553
• 关键词: HIV envelope protein gp120; HIV envelope protein gp41; X ray crystallography; antiAIDS agent; combinatorial chemistry; drug design /synthesis /production; ligands; peptide chemical synthesis; protein structure function; structural biology; synthetic peptide

(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.

（改编自应用）广泛的，长期的目标