Journal
SCIENCE
Volume 323, Issue 5922, Pages 1718-1722Publisher
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/science.1168750
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Funding
- Army [W81XWH-05-1-0316]
- NIH [GM61905, GM078914, GM073197]
- Beckman Foundation
- Skaggs Chemical Biology Foundation
- Jasper L. and Jack Denton Wilson Foundation
- Southwest Cancer and Treatment Center
- Norton B. Gilula Fellowship
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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 similar to 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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