STRUCTURE AND FUNCTION OF CASPASES

半胱天冬酶的结构和功能

• 批准号: 8361676
• 负责人: Jeanne Ann Hardy
• 金额: $ 0.55万
• 依托单位: CORNELL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-04-01 至 2012-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8361676
• 关键词: Active Sites; Allosteric Site; Caspase; Catalysis; Funding; Goals; Grant; Ligands; Molecular; Mutation; National Center for Research Resources; Neurodegenerative Disorders; Principal Investigator; Reaction; Regulation; Reporting; Research; Research Infrastructure; Resources; Role; Source; Structure; United States National Institutes of Health; Work; caspase-6; caspase-7; cost; design; inhibitor/antagonist; mutant; novel; structural biology

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Our current work focuses on caspase-6 and -7. During this reporting period we worked on five main goals for understanding caspase-6 and -7. First, we have designed two new classes of active site inhibitors. We have crystals of caspase-6 with several of these active site inhibitors. Second, we have designed several mutations to probe the role of the structural changes in the 130's and 90's helix in caspase-6. Third, we have crystallized several versions of caspase-6 in a newly inactivated state. Together these structures will help us to understand and ultimately control caspase-6 in neurodegenerative diseases. Forth, we have grown crystals of caspase-7 with a number of novel active-site ligands. The aim of these studies is to understand the reaction mechanism in caspases. To date the molecular details of catalysis remain hazy because the only active site ligands that have been structurally characterized also distort the geometry around the catalytic diad. Fifth we have crystals of several new mutants of caspase-7 that are aimed at helping us to understand the interplay of caspase-7 active-site and allosteric-site regulation.

该副本是利用资源的众多研究子项目之一 由NIH/NCRR资助的中心赠款提供。对该子弹的主要支持 而且，副投影的主要研究员可能是其他来源提供的 包括其他NIH来源。 列出的总费用可能 代表subproject使用的中心基础架构的估计量， NCRR赠款不直接向子弹或副本人员提供的直接资金。 我们目前的工作着重于caspase -6和-7。在此报告期间，我们为了解Caspase -6和-7的五个主要目标致力于。首先，我们设计了两个新的活跃部位抑制剂。我们具有caspase-6的晶体，其中几种活性位点抑制剂。其次，我们设计了几种突变，以探测caspase-6中130年代和90年代螺旋中结构变化的作用。第三，我们在新灭活状态下已经结晶了几种caspase-6的版本。这些结构将共同帮助我们理解并最终控制神经退行性疾病中的caspase-6。第四，我们已经种植了caspase-7的晶体，并具有许多新型的活性位置配体。这些研究的目的是了解胱天蛋白酶中的反应机制。迄今为止，催化的分子细节仍然是朦胧的，因为唯一在结构上表征的活性位点配体也会扭曲催化性Diad周围的几何形状。第五，我们有几个新的caspase-7突变体的晶体，旨在帮助我们了解caspase-7活动位置和变构位置调节的相互作用。