Structure of P-glycoprotein reveals a molecular basis for poly-specific drug binding by Aller Stephen G, Yu Jodie, Ward Andrew, Weng Yue, Chittaboina Srinivas, Zhuo Rupeng, Harrell Patina M, Trinh Yenphuong T, Zhang Qinghai, Urbatsch Ina L, Chang Geoffrey in Science (New York, N.Y.) (2009). PubMed

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 approximately 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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