Structure and function relationships regulating SAMHD1's dual enzymatic activities

调节SAMHD1双酶活性的结构和功能关系

• 批准号: 8992152
• 负责人: jinwoo ahn
• 金额: $ 28.53万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-07-01 至 2020-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8992152
• 关键词: Acquired Immunodeficiency Syndrome; Affect; Allosteric Site; Antiviral Agents; Aspartate; Autoimmune Diseases; Binding; Biochemical; Biological; Biological Assay; CD4 Positive T Lymphocytes; Calorimetry; Catalysis; Catalytic Domain; Cells; Cerebrovascular Disorders; Chronic Lymphocytic Leukemia; DNA Viruses; Data; Enzyme Kinetics; Enzymes; Equilibrium; Foundations; Goals; Guanine; Guanosine Triphosphate; HIV; HIV Infections; HIV-1; Hereditary Disease; Histidine; Immune; Infection; Length; Ligand Binding; Link; Molecular; Mutagenesis; Mutation; Myeloid Cells; N-terminal; Natural Immunity; Nucleic Acid Binding; Nucleotides; Play; Proteins; Publishing; Regulation; Retroviridae; Reverse Transcription; Roentgen Rays; Role; SAM Domain; Site; Stroke; Structure; Structure-Activity Relationship; Substrate Specificity; Surface Plasmon Resonance; Syndrome; Titrations; Viral; Virus Diseases; Work; X-Ray Crystallography; adaptive immunity; base; blocking factor; deoxyribonucleoside triphosphate; design; fighting; insight; leukemia; mutant; novel therapeutic intervention; nuclease; nucleoside triphosphate; public health relevance; therapeutic development

 DESCRIPTION (provided by applicant): SAMHD1 is a deoxyribonucleoside triphosphate (dNTP) triphosphohydrolase. It is a host cell restriction factor that plays critical roles in the defense against human immunodeficiency virus 1 (HIV-1) infection. SAMHD1 lowers the cellular concentrations of dNTP such that effective reverse transcription is prohibited. Interestingly, SAMHD1 also possesses nuclease activity, shown to be essential for its HIV-1 restriction. Understanding the molecular and structural basis of these two important biological activities and their regulation will provide important insight into mechanisms of HIV restriction. To this end, we propose the following Aims: In Aim 1, we will determine the structural basis and molecular mechanisms of SAMHD1 dNTPase activity by nucleoside triphosphates. In Aim 2, the structure-function relationship of the intra- and inter- domain interactions will be investigated. In Aim 3, e will characterize the nuclease activity of SAMHD1 and its structural determinants. Results from this work will provide avenues for designing new therapeutic approaches to fight AIDS.

 描述（由申请人提供）：SAMHD1是脱氧核糖核苷三磷酸（dNTP）三磷酸水解酶。它是一种宿主细胞限制因子，在防御人类免疫缺陷病毒 1 (HIV-1) 感染中发挥着关键作用。 SAMHD1 降低 dNTP 的细胞浓度，从而禁止有效的逆转录。有趣的是，SAMHD1 还具有核酸酶活性，这对其限制 HIV-1 至关重要。了解这两种重要生物活性的分子和结构基础及其调节将为了解 HIV 限制机制提供重要的见解。为此，我们 提出以下目标：在目标1中，我们将通过三磷酸核苷确定SAMHD1 dNTPase活性的结构基础和分子机制。在目标 2 中，将研究域内和域间相互作用的结构-功能关系。在目标 3 中，e 将表征 SAMHD1 的核酸酶活性及其结构决定因素。这项工作的结果将为设计抗击艾滋病的新治疗方法提供途径。