STRUCTURE OF A MEMBRANE TRANSPORTER WITH INHIBITOR

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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.