Structural basis for substrate specificity of single domain APOBEC3s

单域 APOBEC3 底物特异性的结构基础

• 批准号: 9251665
• 负责人: Tania Vanessa Silvas
• 金额: $ 2.88万
• 依托单位: UNIV OF MASSACHUSETTS MED SCH WORCESTER
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-04-01 至 2018-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9251665
• 关键词: AIDS/HIV problem; Active Sites; Adverse effects; Affect; Affinity; Anisotropy; Anti-HIV Agents; Anti-Retroviral Agents; Binding; Biochemical; Biological Assay; Cause of Death; Cells; Chemicals; Chimera organism; Communicable Diseases; Complex; Crystallization; Cytidine; Cytidine Deaminase; Cytosine; DNA; DNA Binding; Deamination; Dependence; Dinucleoside Phosphates; Engineering; Enzymes; Family; Foundations; G-Quartets; HIV; HIV Genome; HIV drug resistance; Homology Modeling; Human; Immune system; Immunity; Mutation; Nucleic Acids; Nucleotides; Probability; Proteins; Publishing; Reverse Transcription; Roentgen Rays; Series; Specificity; Structure; Substrate Specificity; Techniques; Testing; Therapeutic; Uridine; Variant; Viral; Viral Genome; Viral Physiology; Zinc; arm; drug development; experience; innovation; member; preference; public health relevance; skills; success; therapeutic target

 DESCRIPTION (provided by applicant): Structural basis for substrate specificity of single domain APOBEC3s Members of the APOBEC3 (A3) family of cytidine deaminases provide a first line of defense against HIV; however, HIV evades A3 restriction factors through viral infectivity factor (Vif), which antagonizes A3. The overall objective of this proposal is to elucidte the structural basis for substrate specificity of single domain APOBEC3s toward understanding HIV restrictions. A3s can inhibit HIV replication by introducing lethal mutations in the viral genome during reverse transcription. Differences in substrate specificities for deaminating ssDNA among A3 enzymes vary, yet the structural basis for substrate sequence specificity is not well understood. I hypothesize that topological and chemical differences in the active site of A3 enzymes are responsible for their substrate sequence specificities. I propose the following three aims to test my hypothesis: elucidate [1] the substrate sequence dependence of A3 affinity to ssDNA, [2] the mechanism of A3 interaction with substrate ssDNA, and [3] the correlation between homology and specificity of the active site of active A3 Z domains. Results of this proposal will not only contribute to a more comprehensive understanding of the structural basis for A3 function, but will also provide an essential foundation for new innovative anti-HIV drug development strategies.

 描述（由申请人提供）：单结构域 APOBEC3 的底物特异性的结构基础 APOBEC3 (A3) 胞苷脱氨酶家族的成员提供了针对 HIV 的第一道防线；然而，HIV 通过病毒感染因子 (Vif) 逃避 A3 限制因子； ，它拮抗 A3。该提案的总体目标是阐明单域 APOBEC3 的底物特异性的结构基础。 A3 酶可以通过在逆转录过程中在病毒基因组中引入致命突变来抑制 HIV 复制。A3 酶对 ssDNA 脱氨的底物特异性存在差异，但我对这种拓扑结构的底物序列特异性的结构基础还不太了解。 A3 酶活性位点的化学差异导致了它们的底物序列特异性，我提出以下三个目标来检验我的假设： 阐明 [1] A3 亲和力的底物序列依赖性。 ssDNA，[2] A3 与底物 ssDNA 相互作用的机制，以及 [3] 活性 A3 Z 结构域的活性位点的同源性和特异性之间的相关性，该提案的结果不仅有助于更全面地了解结构。 A3 功能的基础，但也将为新的创新抗 HIV 药物开发策略提供重要基础。