Molecular basis of multidrug transport by ATP-binding cassette transporters: a proposed two-cylinder engine model.
ATP-binding cassette multidrug transporters are probably present in all living cells, and are able to export a variety of structurally unrelated compounds at the expense of ATP hydrolysis. The elevated expression of these proteins in multidrug resistant cells interferes with the drug-based control of cancers and infectious pathogenic microorganisms. Multidrug transporters interact directly with the drug substrates. Insights into the structural elements in drug molecules and transport proteins that are required for this interaction are now beginning to emerge. However, much remains to be learned about the nature and number of drug binding sites in the transporters, and the mechanism(s) by which ATP hydrolysis is coupled to changes in affinity and/or accessibility of drug binding sites. This review summarizes recent advances in answering these questions for the human multidrug resistance P-glycoprotein and its prokaryotic homolog LmrA. The relevance of these findings for other ATP-binding cassette transporters will be discussed.
van Veen
H W
HW
Department of Pharmacology, University of Cambridge, UK. hwv20@cam.ac.uk
Higgins
C F
CF
Konings
W N
WN
D018435:ATP Binding Cassette Transporter, Subfamily B / Q000737:chemistry / Q000378:metabolism; D018528:ATP-Binding Cassette Transporters / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D000244:Adenosine Diphosphate / Q000378:metabolism; D000255:Adenosine Triphosphate / Q000378:metabolism*; D000818:Animals; D001426:Bacterial Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D001665:Binding Sites; D004352:Drug Resistance, Microbial; D018432:Drug Resistance, Multiple; D008958:Models, Molecular; D013379:Substrate Specificity
D018435:ATP Binding Cassette Transporter, Subfamily B; D018528:ATP-Binding Cassette Transporters; D001426:Bacterial Proteins; D000244:Adenosine Diphosphate; D000255:Adenosine Triphosphate