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

这个子项目是许多利用资源的研究子项目之一 由NIH/NCRR资助的中心拨款提供。子项目的主要支持 而子项目的主要调查员可能是由其他来源提供的， 包括其它NIH来源。 列出的子项目总成本可能 代表子项目使用的中心基础设施的估计数量， 而不是由NCRR赠款提供给子项目或子项目工作人员的直接资金。 根据该计划提出的实验将产生新的见解，我们的理解的分子机制，Bcl-2蛋白调节的细胞凋亡途径，并建议新的方法来治疗调节这一过程时，异常的癌症和其他疾病。我们将使用Mistic蛋白表达技术以足以进行结构分析的数量生产活性膜整合构象的Bcl-2蛋白。洗涤剂化学和膜蛋白结晶技术的进展将促进这些关键的凋亡调节剂在其功能构象的高分辨率X射线结构测定。这些结构数据将大大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性、膜整合构象下的功能的结构机制，将大大有助于合理设计用于各种疾病的改良药物和新药。

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.