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The Skaggs Institute
for Chemical Biology

Scientific Report 2006

Structural Biology of Transporters and Receptors

G. Chang, Y. Chen, A. Karyakin, X. He, S. Lieu, T. Nguyen, C.L. Reyes, P. Szewczyk, A. Ward, Y. Yin, J. Yu

Determination of the structure of the receptors and efflux transporters involved in maintaining multidrug resistance (MDR) is an important frontier in both molecular structural biology and medicine. We are interested in the structural basis for the transport of drugs and lipids across the cell membrane by MDR transporters and signal transduction by receptors. We use several biochemical techniques, including detergent/lipid protein chromatography, crystallization of membrane proteins, and protein x-ray crystallography. Our experimental strategies include the overexpression, large-scale purification, and 3-dimensional crystallization of these integral membrane proteins.

We have revealed the structures of several structural conformations of the lipid flippase MsbA. MsbA is a bacterial homolog of human MDR1 (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 possible conformational changes. In collaboration with M.G. Finn, the Skaggs Institute, and Q. Zhang, Scripps Research, we are designing inhibitors. Through the help of the Skaggs Institute, we are expanding our structure determinations to incorporate mammalian ATP-binding cassette transporters that confer the MDR phenotype as well as other ATP-binding cassette transporters that are involved in human diseases, including breast cancer. In addition, we are determining the x-ray structures of H+-drug antiporters from the major facilitator superfamily, the multiple antimicrobial toxin extrusion family, and the small multidrug transporter family.

We are also solving the structure of membrane-bound receptors that are important models for signal transduction across the lipid bilayer. Among the families we are working on are the G protein–coupled receptors. Nearly all of these receptors are predicted to have 7 transmembrane helices with domains that bind ligand and activate G proteins. A structure of these receptors will reveal the mechanisms of cell signaling.


Pornillos, O., Chang, G. Inverted repeat domains in membrane proteins. FEBS Lett. 580:358, 2006.

Reyes, C.L., Ward, A., Yu, J., Chang, G. The structures of MsbA: insight into ABC transporter-mediated multidrug efflux. FEBS Lett. 580:1042, 2006.

Yin, Y., He, X., Szewczyk, P., Nguyen, T., Chang, G. Structure of the multidrug transporter EmrD from Escherichia coli. Science 312:741, 2006.


Geoffrey Chang, Ph.D.
Assistant Professor

Chang Web Site