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

American Association for the Advancement of Science (AAAS) - Tập 323 Số 5922 - Trang 1718-1722 - 2009
Stephen G. Aller1,2,3,4, Jodie Yu1,2,3,4, Andrew B. Ward1,2,3,4, Yue Weng1,2,3,4, Srinivas Chittaboina1,2,3,4, Ren Xi Zhuo1,2,3,4, Patina M. Harrell1,2,3,4, Yenphuong T. Trinh1,2,3,4, Qinghai Zhang1,2,3,4, Ina L. Urbatsch1,2,3,4, Geoffrey Chang1,2,3,4
1Cell Biology and Biochemistry, Texas Tech University Health Sciences Center, 3601 4th Street, Lubbock, TX 79430, USA.
2College of Chemistry and Molecular Sciences, Wuhan University, Wuhan 430072, P. R. China
3Department of Cell Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, CB105, La Jolla, CA 92037, USA.
4Department of Molecular Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, CB105, La Jolla, CA 92037, USA.

Tóm tắt

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.

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We thank D. C. Rees I. Wilson R. H. Spencer M. B. Stowell A. Senior A. Frost V. M. Unger C. D. Stout and P. Wright. Y. Weng was supported by a scholarship from P. R. China. We thank Stanford Synchrotron Radiation Lightsource Advanced Light Source and Advanced Photon Source. This work was supported by grants from the Army (W81XWH-05-1-0316) NIH (GM61905 GM078914 and GM073197) the Beckman Foundation the Skaggs Chemical Biology Foundation Jasper L. and Jack Denton Wilson Foundation the Southwest Cancer and Treatment Center and the Norton B. Gilula Fellowship. Coordinates and structure factors deposited to the Protein DataBank (PDB accession codes 3G5U 3G60 and 3G61).

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American Association for the Advancement of Science (AAAS)

Tập 323 Số 5922

1718-1722

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