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The Skaggs Institute
for Chemical Biology

Scientific Report 2005

Structural Biology of Transporters and Receptors

G. Chang, A. Chen, Y. Chen, A. Kariakin, X. He, O. Pornillos, C.L. Reyes, P. Szewczyk, S. Wada, A. Ward, Y. Yin, J. Yu

Determination of the structure of the receptors and efflux transporters involved in multidrug resistance (MDR) is an important and exciting frontier in both molecular structural biology and medicine. We are interested in the structural basis for the transport of hydrophobic substrates across the cell membrane by MDR transporters and signal transduction by receptors. We use several biophysical 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 MsbA, an MDR transporter from the ATP-binding cassette family. 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. 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 cystic fibrosis, breast cancer, and macular dystrophy. 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, which are pharmaceutically important drug targets. Nearly all G protein–coupled 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 on the molecular level.


Pornillos, O., Chen, Y.J., Chen, A.P., Chang, G. X-ray structure of the EmrE multidrug transporter in complex with a substrate. Science 310:1950, 2005.

Reyes, C.L., Chang, G. Lipopolysaccharide stabilizes the crystal packing of the ABC transporter MsbA. Acta Crystallogr. F61:655, 2005.

Reyes, C.L., Chang, G. Structure of the ABC transporter MsbA in complex with ADP•vanadate and lipopolysaccharide. Science 308:1028, 2005.


Geoffrey Chang, Ph.D.
Assistant Professor

Chang Web Site