STRUCTURE AND FUNCTION OF CASPASES

这个子项目是利用资源的许多研究子项目之一。 由NIH/NCRR资助的中心拨款提供。对子项目的主要支持 子项目的首席调查员可能是由其他来源提供的， 包括美国国立卫生研究院的其他来源。为子项目列出的总成本可能 表示该子项目使用的中心基础设施的估计数量， 不是由NCRR赠款提供给次级项目或次级项目工作人员的直接资金。 我们目前的工作重点是caspase-6和caspase-7。在本报告所述期间，我们致力于了解caspase-6和caspase-7的五个主要目标。首先，我们设计了两类新的活性部位抑制剂。我们有caspase-6的晶体，其中有几个活性位点抑制物。第二，我们设计了几个突变来研究caspase-6中130‘S和90’S螺旋结构变化的作用。第三，我们已经结晶了几个版本的caspase-6，处于一种新的失活状态。这些结构将帮助我们理解并最终控制神经退行性疾病中的caspase-6。第四，我们用一些新的活性中心配体生长了caspase-7的晶体。这些研究的目的是为了了解半胱氨酸酶的反应机制。到目前为止，催化的分子细节仍然是模糊的，因为唯一被结构表征的活性中心配体也扭曲了催化二聚体周围的几何结构。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活性位点和变构位点调控的相互作用。

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.