SENP:Conformational Dynamics and Inhibition by Small Molecules

SENP：构象动力学和小分子的抑制

• 批准号: 8829872
• 负责人: Yuan Chen
• 金额: $ 38.43万
• 依托单位: BECKMAN RESEARCH INSTITUTE/CITY OF HOPE
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-05-01 至 2017-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8829872
• 关键词: Acquired Immunodeficiency Syndrome; Address; Affinity; Binding; Binding Sites; Biological; Catalysis; Catalytic Domain; Cleaved cell; Data; Defect; Development; Disease; Drug Design; Drug Kinetics; Drug Targeting; Enzyme Kinetics; Enzymes; Essential Genes; Excision; Family; Future; Goals; Growth and Development function; HIV; Human Genome; Infection; Innovative Therapy; Lead; Life; Life Cycle Stages; Ligands; Malignant Neoplasms; Malignant neoplasm of prostate; Mammals; Modification; Molecular; Molecular Target; Motion; Murine leukemia virus; National Cancer Institute; Peptide Hydrolases; Peptides; Pharmacodynamics; Play; Post-Translational Protein Processing; Process; Production; Protein Dynamics; Protein Family; Proteins; Recycling; Retroviridae; Role; Site-Directed Mutagenesis; Small Interfering RNA; Structure; Structure-Activity Relationship; Therapeutic; Translating; Ubiquitin; United States Food and Drug Administration; United States National Institutes of Health; Viral; analog; angiogenesis; base; cellular targeting; cis trans isomerization; design; enzyme substrate; improved; inhibitor/antagonist; innovation; insight; knock-down; novel therapeutics; particle; protein function; repository; screening; small molecule; sulfoenolpyruvate; virtual

DESCRIPTION (provided by applicant): Post-translational modifications by the SUMO (Small Ubiquitin-like MOdifier) family of proteins are recently discovered essential regulatory mechanisms. During SUMO maturation, a family of SUMO-specific proteases known as SENPs is required for cleaving SUMO precursors. SENPs are also required for removal of SUMO modifications from target proteins. All SENPs in mammals are essential genes, and SENP1 has been shown to play an important role in prostate cancer development and angiogenesis. In preliminary studies, we also identified a role of SENP1 and SENP2 in HIV replication. The goal of this proposal is to improve our understanding of the structure and function of SENPs: their functions in the HIV life cycle, conformational changes and dynamics required for catalysis, and mechanism of inhibition by a group of small molecules. NMR studies in combination with site-directed mutagenesis and enzyme kinetic analysis, as well as molecular biological approaches will be used in these studies. Elucidation of the role of the conformational changes and dynamics required for the SENP catalytic cycle will be the first such study for this large class of enzymes that catalyzes the maturation of ubiquitin-like modifiers and removal of ubiquitin-like modifications. Insights obtained from the proposed studies will not only be fundamentally important for quantitative understanding of an important class of enzymes, but also necessary for rational design and improvement of their inhibitors to enable the development of innovative therapeutics for life-threatening diseases such as cancer and AIDS.

描述（由申请人提供）：蛋白质的Sumo（小型泛素样修饰剂）蛋白质家族的翻译后修饰最近被发现了基本的调节机制。在成熟期间，需要一个被称为SENP的相当特异性蛋白酶的家族才能切割相扑前体。从目标蛋白中去除相扑修饰也需要SENP。哺乳动物中的所有SENP都是必不可少的基因，SENP1已显示在前列腺癌发育和血管生成中起重要作用。在初步研究中，我们还确定了SENP1和SENP2在HIV复制中的作用。该提案的目的是提高我们对SENP的结构和功能的理解：它们在HIV生命周期中的功能，催化所需的构象变化和动力学以及一组小分子抑制的机制。 NMR研究与位置定向的诱变和酶动力学分析以及分子生物学方法相结合。阐明SENP催化循环所需的构象变化和动态的作用将是这类大型研究 催化泛素样修饰剂的成熟并去除泛素样修饰的酶。从拟议的研究中获得的见解不仅对于定量理解重要类别的酶的理解至关重要，而且对于合理的设计和改善其抑制剂也是必要的，以便开发用于危及生命的疾病（如癌症）和艾滋病的创新治疗学。