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The Skaggs Institute
for Chemical Biology

Scientific Report 2007

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

Determining the x-ray structures of multidrug resistance (MDR) transporters is important for the development of future antibiotics. We are interested in the structural basis for the transport of drugs and lipids across the cell membrane by bacterial and mammalian MDR transporters. We use several techniques, including detergent/lipid protein chromatography, crystallization of membrane proteins, and protein x-ray crystallography. Our experimental strategies include the overexpression, purification, and 3-dimensional crystallization of these integral membrane proteins.

We have determined the structures of several conformations of the lipid flippase MsbA. MsbA is a bacterial homolog of human P-glycoprotein, which causes MDR in the treatment of cancer. In collaboration with R. Milligan, Scripps Research, we are using electron cryomicroscopy to study other conformations. In collaboration with M.G. Finn, the Skaggs Institute, and Q. Zhang, Scripps Research, we are designing novel inhibitors. We have also determined the x-ray structures of proton-drug antiporters, including EmrE from the small multidrug transporter family and EmrD from the major facilitator superfamily. We are also working to solve the structures of other bacterial MDR transporters, including those from the multiple antimicrobial toxin extrusion family.

Through the support of the Skaggs Institute, we have expanded our crystallography efforts to include mammalian MDR transporters such as P-glycoprotein that confer resistance in the treatment of several cancers. A single P-glycoprotein molecule contains 2 intracellular nucleotide-binding domains and 2 transmembrane-spanning domains and is independently capable of transporting substrates as a monomer. We recently obtained 3-dimensional crystals of P-glycoprotein and are determining its x-ray structure to facilitate the chemical design of new MDR inhibitors.


Geoffrey Chang, Ph.D.
Assistant Professor

Chang Web Site