Do drug substrates enter the common drug-binding pocket of P-glycoprotein through “gates”?

• Published in: Biochemical and biophysical research communications Vol. 329; no. 2; pp. 419 - 422
• Main Authors: Loo, Tip W., Clarke, David M.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 08.04.2005
• Subjects: Animals; ATP-Binding Cassette, Sub-Family B, Member 1 - chemistry; ATP-Binding Cassette, Sub-Family B, Member 1 - metabolism; Binding Sites; Common drug-binding pocket; Cysteine-scanning mutagenesis; Disulfide cross-linking; Drug Resistance - physiology; Gates; Humans; Ion Channel Gating - physiology; Models, Biological; Models, Chemical; P-glycoprotein; Pharmaceutical Preparations - chemistry; Pharmaceutical Preparations - metabolism; Protein Binding; Protein Conformation; Structure-Activity Relationship; Thiol-reactive analogues; P-glycoprotein; Cysteine-scanning mutagenesis; Disulfide cross-linking; Thiol-reactive analogues; Common drug-binding pocket; Gates
• ISSN: 0006-291X; 1090-2104
• DOI: 10.1016/j.bbrc.2005.01.134

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.