The Skaggs Institute
for Chemical Biology
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
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.
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 proteincoupled
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.