title: Drugs Modulate Interactions between the First Nucleotide-Binding Domain and the Fourth Cytoplasmic Loop of Human P-Glycoprotein.
abstract: Drug substrates stimulate ATPase activity of the P-glycoprotein (P-gp) ATP-binding cassette drug pump by an unknown mechanism. Cross-linking analysis was performed to test if drug substrates stimulate P-gp ATPase activity by altering cross-talk at the first transmission interface linking the drug-binding [intracellular loop 4 (S909C)] and first nucleotide-binding domains [NBD1 (V472C or L443C)]. In the absence of lipid (inactive P-gp), only V472C/S909C showed cross-linking. Drugs blocked V472C/S909C cross-linking. In the presence of lipids (active P-gp), drug substrates promoted only L443C/S909C cross-linking. This suggests that drug substrates stimulate ATPase activity through a conformational change that shifts Ser909 away from Val472 and toward Leu443.
authors.affiliation: Departments of Medicine and Biochemistry, University of Toronto , Toronto, Ontario M5S 1A8, Canada.
authors.forename: Tip W
authors.initials: TW
authors.lastname: Loo
authors.affiliation: Departments of Medicine and Biochemistry, University of Toronto , Toronto, Ontario M5S 1A8, Canada.
authors.forename: David M
authors.initials: DM
authors.lastname: Clarke
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D000251:Adenosine Triphosphatases / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D019943:Amino Acid Substitution; D006801:Humans; D020125:Mutation, Missense; D000072417:Protein Domains; D017433:Protein Structure, Secondary
chemical_list: C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D000251:Adenosine Triphosphatases