Structure and function relationships regulating SAMHD1's dual enzymatic activities

 说明(申请人提供)：SAMHD1是一种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型(HIV-1)感染方面发挥着关键作用。SAMHD1降低了dNTP的细胞浓度，从而抑制了有效的逆转录。有趣的是，SAMHD1还具有核酸酶活性，这是其限制HIV-1所必需的。了解这两种重要生物活性的分子和结构基础及其调控，将为深入了解HIV的限制机制提供重要的启示。为此，我们 提出以下目标：在目标1中，我们将确定核苷三磷酸对SAMHD1 dNTPase活性的结构基础和分子机制。在目标2中，将研究结构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。

 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.