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

Science
27 Mar 2009
Vol 323, Issue 5922
pp. 1718-1722

Abstract

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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Information & Authors

Information

Published In

Science
Volume 323 | Issue 5922
27 March 2009

Submission history

Received: 19 November 2008
Accepted: 17 February 2009
Published in print: 27 March 2009

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Notes

Supporting Online Material
www.sciencemag.org/cgi/content/full/323/5922/1718/DC1
Materials and Methods
Figs. S1 to S20
Tables S1 to S3
References

Authors

Affiliations

Stephen G. Aller
Department of Molecular Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, CB105, La Jolla, CA 92037, USA.
Jodie Yu
Department of Molecular Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, CB105, La Jolla, CA 92037, USA.
Andrew Ward
Department of Cell Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, CB105, La Jolla, CA 92037, USA.
Yue Weng
Department of Molecular Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, CB105, La Jolla, CA 92037, USA.
College of Chemistry and Molecular Sciences, Wuhan University, Wuhan, 430072 P. R. China.
Srinivas Chittaboina
Department of Molecular Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, CB105, La Jolla, CA 92037, USA.
Rupeng Zhuo
Cell Biology and Biochemistry, Texas Tech University Health Sciences Center, 3601 4th Street, Lubbock, TX 79430, USA.
Patina M. Harrell
Cell Biology and Biochemistry, Texas Tech University Health Sciences Center, 3601 4th Street, Lubbock, TX 79430, USA.
Yenphuong T. Trinh
Cell Biology and Biochemistry, Texas Tech University Health Sciences Center, 3601 4th Street, Lubbock, TX 79430, USA.
Qinghai Zhang
Department of Molecular Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, CB105, La Jolla, CA 92037, USA.
Ina L. Urbatsch
Cell Biology and Biochemistry, Texas Tech University Health Sciences Center, 3601 4th Street, Lubbock, TX 79430, USA.
Geoffrey Chang [email protected]
Department of Molecular Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, CB105, La Jolla, CA 92037, USA.

Notes

To whom correspondence should be addressed. E-mail: [email protected]

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