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