STRUCTURE OF A MEMBRANE TRANSPORTER WITH INHIBITOR

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 CLC氯转运蛋白协调氯的运动，是正常的神经元、肌肉、心血管和上皮功能所必需的。确定了大肠杆菌CLC(ClC-EC1)与Fab片段形成的复合体的结构(PdB 10OTS)。在NIH(1R01GM070773-01A2)资助的工作中，我们发现了几种ClC-EC1的抑制剂。我们现在建议确定CLC-EC1/抑制剂复合体的结构。这些实验的结果将提供CLC抑制剂结合位点的第一个结构。这种结构将有助于使用抑制剂作为工具来探索ClC-EC1中的氯运输机制，并可能被证明有助于定位哺乳动物同系物中的抑制剂结合部位。此外，该结构可能有助于设计具有更好的亲和力和特异性的抑制剂，而这是CLCs所严重缺乏的。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The CLC chloride-transport proteins orchestrate the movement of chloride necessary for proper neuronal, muscular, cardiovascular, and epithelial function. The structure of an E. coli CLC (CLC-ec1) in complex with a Fab fragment has been determined (pdb 1OTS). In work funded by the NIH (1R01GM070773-01A2), we have discovered several inhibitors of CLC-ec1. We now propose to determine the structure of the ClC-ec1/inhibitor complex. The results of these experiments will provide the first structure of a CLC inhibitor binding site. This structure will facilitate the use of inhibitors as tools to probe the chloride-transport mechanism in CLC-ec1, and could also prove useful for mapping the inhibitor-binding site in the mammalian homologs. In addition, the structure may aid in designing inhibitors with improved affinity and specificity, which are sorely lacking for the CLCs.