STRUCTURE DETERMINATION OF MEMBRANE-INTEGRATING FORMS OF BCL-2 PROTEINS

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。 该计划下提出的实验将为我们理解Bcl-2蛋白调节线粒体介导的细胞凋亡途径的分子机制提供新的见解，并提出在癌症和其他疾病中发生异常时从治疗上调节这一过程的新方法。我们将使用Mistic蛋白质表达技术，以足够的数量生产活性的、膜整合构象的Bcl-2蛋白质，以进行结构分析。洗涤剂化学和膜蛋白结晶技术的进展将有助于高分辨X射线结构确定这些关键的凋亡调节因子的功能构象。这些结构数据将极大地提高我们对这些蛋白质控制线粒体膜通透性以调节细胞死亡途径的理解。更深入地了解这些蛋白质在其活跃的、膜整合的构象中的潜在功能的结构机制，将大大有助于改进药物和治疗各种疾病的新型药物的合理设计。

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. The experiments proposed under this program will produce new insights into our understanding of the molecular mechanisms by which Bcl-2 proteins regulate the mitochondria-mediated apoptotic pathway and suggest new approaches to therapeutically modulating this process when aberrant in cancer and other diseases. We will use the Mistic protein expression technology to produce Bcl-2 proteins in active, membrane-integrated conformations at quantities sufficient for structural analysis. Advances in detergent chemistry and membrane protein crystallization techniques will facilitate high resolution X-ray structure determination of these critical apoptotic regulators in their functional conformations. This structural data will greatly improve our understanding of the means by which these proteins control mitochondria membrane permeability to regulate cellular death pathways. Greater insight into the structural mechanisms underlying the function of these proteins when in their active, membrane-integrated conformations will substantially aid the rational design of improved drugs and novel medicines for a broad variety of illnesses.