Structure of Small Multidrug Resistance Transporters

描述（由申请人提供）： 细菌多药耐药（MDR）现象是一个重要的健康问题，威胁着逆转治疗感染性疾病的医学进步。MDR的主要原因之一是通过MDR转运蛋白的作用，MDR转运蛋白是主动将药物和抗生素转运出细胞的膜蛋白。在这些MDR转运蛋白中，小多药耐药（SMR）外排泵是最小的，具有最简单的组织。SMR充当质子-药物反向转运体，并将药物挤出耦合到穿过细菌细胞膜的质子电化学梯度。E. coli EmrE蛋白的研究首次揭示了SMR泵的结构，并揭示了由倒置单体组成的不寻常的二聚体。还有几个重要问题。SMR泵如何识别和结合药物底物？药物结合后会发生什么构象变化？毒品出口如何与质子进口相结合？为了开始回答这些问题，我们建议确定额外的SMR蛋白在其未结合和药物结合形式的结构。我们希望这些研究将提供一个详细的结构框架，了解SMR转运蛋白的功能。

DESCRIPTION (provided by applicant): The phenomenon of bacterial multidrug resistance (MDR) is an important health problem that threatens to reverse medical progress in treating infectious diseases. One of the major causes of MDR is through the action of MDR transporters, which are membrane proteins that actively transport drugs and antibiotics out of the cell. Of these MDR transporters, the Small Multidrug Resistance (SMR) efflux pumps are the smallest and have the simplest organization. SMRs act as proton-drug antiporters, and couple drug extrusion to the proton electrochemical gradient across bacterial cell membranes. Recent structures of the E. coli EmrE protein have provided a first glimpse of the architecture of SMR pumps, and reveal an unusual dimer composed of inverted monomers. Several important questions remain. How do SMR pumps recognize and bind drug substrates? What conformational changes occur upon drug binding? How is drug export coupled to proton import? To begin to answer these questions, we propose to determine the structures of additional SMR proteins in their unbound and drug-bound forms. We hope that these studies would provide a detailed structural framework for understanding the function SMR transporters.