Structural studies of biomolecules related to cancer and HIV-AIDS

与癌症和艾滋病相关的生物分子的结构研究

• 批准号: 9344057
• 负责人: Hiroshi Matsuo
• 金额: $ 74.54万
• 依托单位: DIVISION OF BASIC SCIENCES - NCI
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/9344057
• 关键词: AIDS/HIV problem; APOCEC3G gene; Acquired Immunodeficiency Syndrome; Binding; Biochemical; Catalytic Domain; Complex; Conflict (Psychology); Cytosine deaminase; DNA; Defense Mechanisms; Epitopes; Genome; Goals; HIV; HIV-1; Human; Infection; Magnetism; Malignant Neoplasms; Mutate; Nuclear; Pathway interactions; Proteins; RNA; Research; Research Project Grants; Single-Stranded DNA; Spectrum Analysis; Structure; Techniques; Ubiquitin; Virion; Work; X-Ray Crystallography; multicatalytic endopeptidase complex; novel therapeutics; pathogen; protein structure; ubiquitin-protein ligase

A3G is a single-stranded DNA cytosine deaminase that can restrict HIV-1 infection by mutating HIV-1 genome. HIV-1 developed a counter defense mechanism by which virion infectivity factor (Vif) leads the degradation of A3G through ubiquitin-proteasome pathway. Our ultimate goal is to generate small compounds which inhibit the degradation of A3G. We have determined structures of two functional domains of A3G, including the VIf-binding domain and the catalytic domain. We have been working toward the structure determination of the A3G-Vif E3 ubiquitin ligase complex that will provide epitopes to be targeted by small compounds which inhibit formation of the complex. The A3G-Vif E3 ubiquitin ligase complex contains 6 proteins, and therefore it is challenging for any structural study. We are developing and optimizing biochemical and spectroscopic techniques to overcome the challenge.

A3G是一种单链DNA胞嘧啶脱氨酶，可以通过突变HIV-1基因组来限制HIV-1感染。 HIV-1 形成了一种反防御机制，病毒颗粒感染因子 (Vif) 通过泛素-蛋白酶体途径导致 A3G 降解。我们的最终目标是产生抑制 A3G 降解的小化合物。我们已经确定了 A3G 的两个功能域的结构，包括 VIf 结合域和催化域。我们一直致力于确定 A3G-Vif E3 泛素连接酶复合物的结构，该复合物将提供抑制复合物形成的小化合物靶向的表位。 A3G-Vif E3 泛素连接酶复合物包含 6 个蛋白质，因此对于任何结构研究都具有挑战性。我们正在开发和优化生化和光谱技术来克服这一挑战。