STRUCTURAL STUDIES OF INTERACTIONS AMONG BCL-2 FAMILY 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。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 表示子项目使用的中心基础设施的估计数量， NCRR赠款不直接向子项目或子项目工作人员提供资金。 Keating实验室的研究旨在了解人类Bcl-2家族蛋白之间相互作用特异性的决定因素。Bcl-2蛋白调节大肠杆菌，并已成为重要的抗癌药物靶点。我们正在研究从促凋亡Bcl-2蛋白的BH 3区域衍生的短α-螺旋肽与抗凋亡家族成员的结合。我们进行了结合研究和结构研究，并将这些与计算方法联合收割机结合起来，以更好地了解序列如何决定相互作用的特异性。X射线晶体学研究是这项工作的关键组成部分，因为结构提供了对受体蛋白如何调整以结合一系列不同配体的见解。由于新的结构快照可以为肽或小分子药物设计提供机会，因此这些研究对开发新的治疗和诊断药物具有重要意义。

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. Research in the Keating lab aims to understand determinants of interaction specificity among human Bcl-2 family proteins. The Bcl-2 proteins regulate apoptotis and have emerged as important anti-cancer drug targets. We are studying the binding of short alpha-helical peptides derived from the BH3 region of pro-apoptotic Bcl-2 proteins to anti-apoptotic family members. We carry out binding studies and structural studies and combine these with computational methods to obtain a better understanding of how sequence determines interaction specificity. X-ray crystallographic studies are a key component of this work, as structure provides insights into how the receptor proteins can adjust to bind a range of different ligands. Because new structural snapshots can provide opportunities for peptide or small-molecule drug design, these studies have implications for the development of new therapeutics and diagnotics.