title: Do drug substrates enter the common drug-binding pocket of P-glycoprotein through "gates"?
abstract: Overexpression of P-glycoprotein (P-gp; ABCB1) can cause multidrug resistance during cancer and AIDS chemotherapy because of its ability to transport a broad range of structurally unrelated compounds from the cell. P-gp is a member of the ABC family of proteins. It is a single polypeptide containing four domains--two transmembrane (TM) domains each of which contains six TM segments, and two nucleotide-binding domains. Chemical modification and cross-linking studies of cysteine mutants of P-gp indicate that the common drug-binding pocket is at the interface between the TM domains. It has been postulated that drug substrates enter the lipid bilayer, are extracted by P-gp and transported to the extracellular medium. It is not clear how drug substrates enter the drug-binding pocket. Here, we propose that drug-substrates diffuse from the lipid bilayer into the drug-binding pocket through "gates" formed by TM segments at either end of the drug-binding pocket.
authors.affiliation: Department of Medicine, University of Toronto, Toronto, Ontario, Canada M5S 1A8.
authors.forename: Tip W
authors.initials: TW
authors.lastname: Loo
authors.forename: David M
authors.initials: DM
authors.lastname: Clarke
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000737:chemistry* / Q000378:metabolism*; D000818:Animals; D001665:Binding Sites; D004351:Drug Resistance / Q000502:physiology; D006801:Humans; D015640:Ion Channel Gating / Q000502:physiology*; D008954:Models, Biological; D008956:Models, Chemical; D004364:Pharmaceutical Preparations / Q000737:chemistry* / Q000378:metabolism*; D011485:Protein Binding; D011487:Protein Conformation; D013329:Structure-Activity Relationship
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D004364:Pharmaceutical Preparations