SENP:Conformational Dynamics and Inhibition by Small Molecules

描述（由申请人提供）：SUMO（小泛素样调节剂）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，需要一个称为SENP的SUMO特异性蛋白酶家族来切割SUMO前体。SENP也是从靶蛋白中去除SUMO修饰所必需的。哺乳动物中的所有SENP都是必需基因，并且SENP 1已被证明在前列腺癌的发展和血管生成中起重要作用。在初步研究中，我们还确定了SENP 1和SENP 2在HIV复制中的作用。该提案的目标是提高我们对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，以及一组小分子的抑制机制。在这些研究中，将使用NMR研究结合定点诱变和酶动力学分析，以及分子生物学方法。阐明SENP催化循环所需的构象变化和动力学的作用将是这一大类化合物的首次此类研究。 催化泛素样修饰物成熟和去除泛素样修饰的酶。从拟议的研究中获得的见解不仅对定量了解一类重要的酶具有根本重要性，而且对合理设计和改进其抑制剂，以开发癌症和艾滋病等危及生命的疾病的创新疗法也是必要的。

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.