Structure of Small Multidrug Resistance Transporters

小型多药耐药转运蛋白的结构

• 批准号: 6936286
• 负责人: Owen Pornillos
• 金额: $ 3.61万
• 依托单位: SCRIPPS RESEARCH INSTITUTE, THE
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-04-01 至 2005-12-15
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6936286
• 关键词: Bacillus subtilis; Bordetella pertussis; Escherichia coli; Mycobacterium tuberculosis; X ray crystallography; active transport; antiport; bacterial proteins; binding sites; conformation; dimer; electrochemistry; ethidium; hydrogen transport; lipid bilayer membrane; membrane transport proteins; multidrug resistance; postdoctoral investigator; protein structure function; species difference; structural biology; synchrotrons

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.

描述（由申请人提供）： 细菌多药耐药性（MDR）现象是一个重要的健康问题，有可能逆转传染病治疗方面的医学进展。 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，小型多药耐药 (SMR) 外排泵是最小的且具有最简单的组织。 SMR 充当质子药物反向转运蛋白，并将药物挤出与穿过细菌细胞膜的质子电化学梯度耦合。大肠杆菌 EmrE 蛋白的最新结构让人们对 SMR 泵的结构有了初步了解，并揭示了一种由反向单体组成的不寻常的二聚体。仍有几个重要问题需要解决。 SMR泵如何识别并结合药物底物？药物结合后会发生哪些构象变化？药物出口与质子进口如何耦合？为了开始回答这些问题，我们建议确定其他 SMR 蛋白未结合和药物结合形式的结构。我们希望这些研究能够为理解 SMR 转运蛋白的功能提供详细的结构框架。