title: Structure of P-glycoprotein reveals a molecular basis for poly-specific drug binding.
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.
authors.affiliation: Department of Molecular Biology, Scripps Research Institute, 10550 North Torrey Pines Road, CB105, La Jolla, CA 92037, USA.
authors.forename: Stephen G
authors.initials: SG
authors.lastname: Aller
authors.forename: Jodie
authors.initials: J
authors.lastname: Yu
authors.forename: Andrew
authors.initials: A
authors.lastname: Ward
authors.forename: Yue
authors.initials: Y
authors.lastname: Weng
authors.forename: Srinivas
authors.initials: S
authors.lastname: Chittaboina
authors.forename: Rupeng
authors.initials: R
authors.lastname: Zhuo
authors.forename: Patina M
authors.initials: PM
authors.lastname: Harrell
authors.forename: Yenphuong T
authors.initials: YT
authors.lastname: Trinh
authors.forename: Qinghai
authors.initials: Q
authors.lastname: Zhang
authors.forename: Ina L
authors.initials: IL
authors.lastname: Urbatsch
authors.forename: Geoffrey
authors.initials: G
authors.lastname: Chang