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

基本信息

批准号：
9100863
负责人：
jinwoo ahn
金额：
$ 28.49万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
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/9100863
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 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 pseudotoxoplasmosis syndrome public health relevance therapeutic development

项目摘要

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（由适用提供）：SAMHD1是三磷酸三磷酸（DNTP）三磷酶的脱氧核苷。这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）感染中起着关键作用。 SAMHD1降低了DNTP的细胞浓度，因此禁止有效的逆转录。有趣的是，SAMHD1还具有核酸酶活性，这对于其HIV-1限制至关重要。了解这两种重要的生物学活性的分子和结构基础及其调节将为HIV限制机制提供重要的见解。为此，我们提出以下目的：在AIM 1中，我们将通过核苷三磷酸盐确定SAMHD1 DNTPase活性的结构基础和分子机制。在AIM 2中，将研究内部和域间相互作用的结构功能关系。在AIM 3中，E将表征SAMHD1及其结构决定剂的核苷活性。这项工作的结果将为设计新的治疗方法来打击艾滋病。