The power of the pump: mechanisms of action of P-glycoprotein (ABCB1).
Members of the superfamily of ATP-binding cassette (ABC) transporters mediate the movement of a variety of substrates including simple ions, complex lipids and xenobiotics. At least 18 ABC transport proteins are associated with disease conditions. P-glycoprotein (Pgp, ABCB1) is the archetypical mammalian ABC transport protein and its mechanism of action has received considerable attention. There is strong biochemical evidence that Pgp moves molecular cargo against a concentration gradient using the energy of ATP hydrolysis. However, the molecular details of how the energy of ATP hydrolysis is coupled to transport remain in dispute and it has not been possible to reconcile the data from various laboratories into a single model. The functional unit of Pgp consists of two nucleotide binding domains (NBDs) and two trans-membrane domains which are involved in the transport of drug substrates. Considerable progress has been made in recent years in characterizing these functionally and spatially distinct domains of Pgp. In addition, our understanding of the domains has been augmented by the resolution of structures of several non-mammalian ABC proteins. This review considers: (i) the role of specific conserved amino acids in ATP hydrolysis mediated by Pgp; (ii) emerging insights into the dimensions of the drug binding pocket and the interactions between Pgp and the transport substrates and (iii) our current understanding of the mechanisms of coupling between energy derived from ATP binding and/or hydrolysis and efflux of drug substrates.
Ambudkar
Suresh V
SV
Laboratory of Cell Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, DHHS, Bethesda, MD 20892-4256, USA. ambudkar@helix.nih.gov
Kim
In-Wha
IW
Sauna
Zuben E
ZE
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000737:chemistry / Q000378:metabolism*; D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites; D001692:Biological Transport; D017124:Conserved Sequence; D004252:DNA Mutational Analysis; D006801:Humans; D008954:Models, Biological; D009711:Nucleotides / Q000378:metabolism; D004364:Pharmaceutical Preparations / Q000378:metabolism*; D017434:Protein Structure, Tertiary
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D009711:Nucleotides; D004364:Pharmaceutical Preparations