SENP:Conformational Dynamics and Inhibition by Small Molecules

描述（由申请人提供）：SUMO （Small Ubiquitin-like MOdifier）蛋白家族的翻译后修饰是最近发现的重要调控机制。在SUMO成熟过程中，SUMO特异性蛋白酶家族（称为SENPs）是切割SUMO前体所必需的。从靶蛋白中去除SUMO修饰也需要SENPs。哺乳动物中所有的SENPs都是必需基因，SENP1在前列腺癌的发展和血管生成中发挥重要作用。在初步研究中，我们还发现了SENP1和SENP2在HIV复制中的作用。本研究的目的是提高我们对SENPs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，以及一组小分子的抑制机制。核磁共振研究结合定点诱变和酶动力学分析，以及分子生物学方法将在这些研究中使用。阐明SENP催化循环所需的构象变化和动力学的作用将是这类大型生物的第一次此类研究

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.