Structure of P-glycoprotein reveals a molecular basis for poly-specific drug binding

Academic Article

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.
  • Published In

  • Science  Journal
  • Digital Object Identifier (doi)

    Author List

  • Aller SG; Yu J; Ward A; Weng Y; Chittaboina S; Zhuo R; Harrell PM; Trinh YT; Zhang Q; Urbatsch IL
  • Start Page

  • 1718
  • End Page

  • 1722
  • Volume

  • 323
  • Issue

  • 5922