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Science 27 March 2009:
Vol. 323. no. 5922, pp. 1718 - 1722
DOI: 10.1126/science.1168750
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Reports

Structure of P-Glycoprotein Reveals a Molecular Basis for Poly-Specific Drug Binding

Stephen G. Aller,1 Jodie Yu,1 Andrew Ward,2 Yue Weng,1,4 Srinivas Chittaboina,1 Rupeng Zhuo,3 Patina M. Harrell,3 Yenphuong T. Trinh,3 Qinghai Zhang,1 Ina L. Urbatsch,3 Geoffrey Chang1{dagger}

P-glycoprotein (P-gp) detoxifies cells by exporting hundreds of chemically unrelated toxins but has been implicated in multidrug resistance (MDR) in the treatment of cancers. Substrate promiscuity is a hallmark of P-gp activity, thus a structural description of poly-specific drug-binding is important for the rational design of anticancer drugs and MDR inhibitors. The x-ray structure of apo P-gp at 3.8 angstroms reveals an internal cavity of ~6000 angstroms cubed with a 30 angstrom separation of the two nucleotide-binding domains. Two additional P-gp structures with cyclic peptide inhibitors demonstrate distinct drug-binding sites in the internal cavity capable of stereoselectivity that is based on hydrophobic and aromatic interactions. Apo and drug-bound P-gp 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.

1 Department of Molecular Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, CB105, La Jolla, CA 92037, USA.
2 Department of Cell Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, CB105, La Jolla, CA 92037, USA.
3 Cell Biology and Biochemistry, Texas Tech University Health Sciences Center, 3601 4th Street, Lubbock, TX 79430, USA.
4 College of Chemistry and Molecular Sciences, Wuhan University, Wuhan, 430072 P. R. China.

{dagger} To whom correspondence should be addressed. E-mail: gchang{at}scripps.edu

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