The Skaggs Institute
for Chemical Biology

Scientific Report 2008

Structure and Biology of Multidrug Transporters

G. Chang, S. Aller, Y. Chen, X. He, A. Karyakin, S. Lieu, T. Nguyen, M. Revin, P. Szewczyk, A. Ward, J. Yu

Multidrug resistance (MDR) is a major clinical problem in the chemotherapy of infection and cancer. The structural characterization of MDR transporters is important for the development of future compounds to reverse drug resistance. We are interested in the molecular basis of the transport of drugs and lipids across the cell membrane by bacterial and mammalian MDR transporters. We combine structure, function, and chemistry through collaborations with M.G. Finn, the Skaggs Institute, and Q. Zhang, Scripps Research. We use several techniques, including detergent/lipid protein chromatography, membrane protein crystallization, and x-ray crystallography.

We have already solved the molecular structures of several conformations of the lipid flippase MsbA, a member of the ATP-binding cassette transporter family. We are also using electron cryomicroscopy, in collaboration with R. Milligan, Scripps Research, to study other conformations. In addition, we have determined the
x-ray structures of proton-drug antiporters, including EmrE from the small multidrug resistance transporter family and EmrD from the major facilitator superfamily. We recently determined the x-ray structure of P-glycoprotein in complexes with drugs to understand the structural basis of polyspecificity.

With support from the Skaggs Institute, we have focused on determining the structure of a bacterial MDR transporter from the multiple antimicrobial toxin extrusion family, which has important clinical relevance. This family is the last family of MDR transporters whose structure has not yet been characterized, and these transporters play an important role in the efflux of a variety of antibiotic compounds, including fluoroquinolones. MDR transporters from this family also efflux antimicrobial compounds in plants as part of the plants' natural defense mechanism against microbes. A structure of the bacterial transporter would greatly aid the rational design of inhibitors to reverse MDR in the treatment of infection.