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

Science. 2009 Mar 27;323(5922):1718-22. doi: 10.1126/science.1168750.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily B, Member 1 / antagonists & inhibitors
  • ATP Binding Cassette Transporter, Subfamily B, Member 1 / chemistry*
  • ATP Binding Cassette Transporter, Subfamily B, Member 1 / metabolism*
  • Adenosine Triphosphate / metabolism
  • Amino Acid Sequence
  • Animals
  • Apoproteins / chemistry
  • Apoproteins / metabolism
  • Binding Sites
  • Cell Membrane / chemistry
  • Crystallography, X-Ray
  • Hydrophobic and Hydrophilic Interactions
  • Lipid Bilayers / chemistry
  • Mice
  • Models, Molecular
  • Molecular Sequence Data
  • Peptides, Cyclic / chemistry*
  • Peptides, Cyclic / metabolism*
  • Protein Binding
  • Protein Conformation
  • Protein Structure, Secondary
  • Protein Structure, Tertiary
  • Stereoisomerism
  • Verapamil / metabolism
  • Verapamil / pharmacology

Substances

  • ATP Binding Cassette Transporter, Subfamily B, Member 1
  • Apoproteins
  • Lipid Bilayers
  • Peptides, Cyclic
  • cyclic-tris-(R)-valineselenazole
  • Adenosine Triphosphate
  • Verapamil

Associated data

  • PDB/3G5U
  • PDB/3G60
  • PDB/3G61