SENP:Conformational Dynamics and Inhibition by Small Molecules

SENP：构象动力学和小分子的抑制

基本信息

批准号：
8454447
负责人：
Yuan Chen
金额：
$ 37.09万
依托单位：
BECKMAN RESEARCH INSTITUTE/CITY OF HOPE
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-05-01 至 2016-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8454447
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

项目摘要

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）：SUMO（小泛素样修饰剂）蛋白家族的翻译后修饰是最近发现的重要调节机制。在 SUMO 成熟过程中，需要称为 SENP 的 SUMO 特异性蛋白酶家族来裂解 SUMO 前体。 SENP 还需要从目标蛋白中去除 SUMO 修饰。哺乳动物中的所有 SENP 都是必需基因，SENP1 已被证明在前列腺癌发展和血管生成中发挥重要作用。在初步研究中，我们还确定了 SENP1 和 SENP2 在 HIV 复制中的作用。该提案的目标是提高我们对 SENP 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，以及一组小分子的抑制机制。这些研究将采用核磁共振研究与定点突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力学的作用将是针对这一大类物质的首次此类研究。催化泛素样修饰物成熟和去除泛素样修饰的酶。从拟议研究中获得的见解不仅对于定量理解一类重要的酶具有根本性的重要意义，而且对于合理设计和改进其抑制剂以开发针对癌症和艾滋病等危及生命的疾病的创新疗法也是必要的。