Structure of Small Multidrug Resistance Transporters

Scripps Research Institute, La Jolla CA

Investigators

Abstract

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.