P-glycoprotein (Pgp) detoxifies cells by exporting hundreds of chemically unrelated toxins but has been implicated in multidrug resistance in the treatment of cancers. Substrate promiscuity is a hallmark of Pgp activity, thus a structural description of polyspecific drug-binding is important for the rational design of anticancer drugs and MDR inhibitors. The x-ray structure of apo-Pgp at 3.8 Å reveals an internal cavity of ~6,000 Å3 with a 30 Å separation of the two nucleotide binding domains (NBD). Two additional Pgp structures with cyclic peptide inhibitors demonstrate distinct drug binding sites in the internal cavity capable of stereo-selectivity that is based on hydrophobic and aromatic interactions. Apo- and drug-bound Pgp structures have portals open to the cytoplasm and the inner leaflet of the lipid bilayer for drug entry. The inward-facing conformation represents an initial stage of the transport cycle that is competent for drug binding. We will present our latest findings on P-glycoprotein and present strategy on obtaining other conformations, extending the diffraction resolution, and new co-crystal structures with inhibitors/drugs.
University of Manchester (2010) Proc Physiol Soc 19, SA16
Research Symposium: Structure of P-glycoprotein
G. Chang1, A. Ward1, S. G. Aller1, J. Yu1, Y. Weng2, S. Chittaboina1, R. Zhuo3, P. M. Harrell3, Y. T. Trinh3, Q. Zhang1, I. Urbatsch3
1. Molecular Biology, The Scripps Research Institute, La Jolla, California, United States. 2. College of Chemistry and Molecular Sciences Wuhan University, Wuhan, China. 3. Texas Tech Univeristy Health Sciences Center, Lubbock, Texas, United States.
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