title: New insights into the drug binding, transport and lipid flippase activities of the p-glycoprotein multidrug transporter.
abstract: The MDR1 P-glycoprotein, an ATP-binding cassette (ABC) superfamily member that functions as an ATP-driven drug efflux pump, has been linked to resistance of human tumors to multiple chemotherapeutic agents. P-glycoprotein binds and actively transports a large variety of hydrophobic drugs and peptides. P-glycoprotein in reconstituted proteoliposomes is also an outwardly directed flippase for membrane phospholipids and simple glycosphinglipids. This review focuses on recent advances in our understanding of P-glycoprotein structure and function, particularly through the use of fluorescence spectroscopic approaches. Progress is being made towards understanding the structure of the transporter, especially the spatial relationship between the two nucleotide-binding domains. Exploration of the P-glycoprotein catalytic cycle using vanadate-trapped complexes has revealed that drug transport likely takes place by concerted conformational changes linked to relaxation of a high energy intermediate. Low resolution mapping of the protein using fluorescence resonance energy transfer showed that both the H and R drug-binding sites are located within the cytoplasmic leaflet. Two drugs can bind to the R-site simultaneously, suggesting that the protein contains a large flexible binding region.
authors.affiliation: Department of Molecular and Cellular Biology, University of Guelph, Science Complex Room 2255, Guelph, Ontario, Canada. fsharom@uoguelph.ca
authors.forename: Frances J
authors.initials: FJ
authors.lastname: Sharom
authors.forename: Miguel R
authors.initials: MR
authors.lastname: Lugo
authors.forename: Paul D W
authors.initials: PD
authors.lastname: Eckford
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000737:chemistry* / Q000378:metabolism*; D001665:Binding Sites; D001692:Biological Transport; D031541:Fluorescence Resonance Energy Transfer; D006801:Humans; D049294:Phospholipid Transfer Proteins / Q000378:metabolism
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D049294:Phospholipid Transfer Proteins