THE VANDERBILT UNIVERSITY

This administrative supplement requests funds to accelerate research on the structural dynamics of multidrug ABC tranporters (R01-GM077569). Active drug extrusion by multidrug transporters is one of four general mechanisms associated with the multidrug resistance (MDR) phenomenon, a key clinical obstacle in the treatment of bacterial and fungal infections and cancers. The long term goal of this research program is to elucidate the mechanism of a class of multidrug transporters, the adenosine triphosphate (ATP) binding cassette (ABC) transporters, that is associated with a number of human pathologies in addition to its critical role in removal of cytotoxic agents. ABC transporters transduce the energy of ATP binding and hydrolysis into the mechanical work of substrate translocation across cell membranes. Roughly 5% of the E. coli genome encodes for ABC transporters; one of which, MsbA, uses ATP energy to flip the building block of the outer membrane, lipid A, across the inner membrane. Its indispensable role in bacterial viability and growth, sequence and functional similarity to human multidrug transporters such as p-glycoprotein in conjunction with extensive crystallographic analysis make MsbA a biochemically and biophysically tractable model of clinically relevant ATP-coupled transport. The research activities to be supoprted by this supplement are to use state of the art electron paramagnetic resonance spectroscopy to detemine the dynamics and accessibility of MsbA during the transport cycle. New lumniscence resonance energy transfer instrumentation will facilitate the completion of aims designed to measure distances changes across MsbA domains upon ATP binding. An undrepresented minority graduate student will be supported to carry out IRG-approved research activities using these techniques.

Clarification of Codes