This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Sauna, Z. E. Articles by Ambudkar, S. V. Search for Related Content PubMed PubMed Citation Articles by Sauna, Z. E. Articles by Ambudkar, S. V. Related Collections Therapeutics and Targets Therapeutics and Targets: Drug Mechanisms and Resistance

Reviews

About a switch: how P-glycoprotein (ABCB1) harnesses the energy of ATP binding and hydrolysis to do mechanical work

Laboratory of Cell Biology, Center for Cancer Research, National Cancer Institute, NIH, Department of Health and Human Services, Bethesda, Maryland

Requests for reprints: Suresh V. Ambudkar, Laboratory of Cell Biology, Center for Cancer Research, National Cancer Institute, NIH, Building 37, Room 2120, 37 Convent Drive, Bethesda, MD 20892-4256. Phone: 301-402-4178; Fax: 301-435-8188. E-mail: ambudkar{at}helix.nih.gov

The efflux of drugs by the multidrug transporter P-glycoprotein (Pgp; ABCB1) is one of the principal means by which cancer cells evade chemotherapy and exhibit multidrug resistance. Mechanistic studies of Pgp-mediated transport, however, transcend the importance of this protein per se as they help us understand the transport pathway of the ATP-binding cassette proteins in general. The ATP-binding cassette proteins comprise one of the largest protein families, are central to cellular physiology, and constitute important drug targets. The functional unit of Pgp consists of two nucleotide-binding domains (NBD) and two transmembrane domains that are involved in the transport of drug substrates. Early studies postulated that conformational changes as a result of ATP hydrolysis were transmitted to the transmembrane domains bringing about drug transport. More recent structural and biochemical studies on the other hand suggested that ATP binds at the interface of the two NBDs and induces the formation of a closed dimer, and it has been hypothesized that this dimerization and subsequent ATP hydrolysis powers transport. Based on the mutational and biochemical work on Pgp and structural studies with isolated NBDs, we review proposed schemes for the catalytic cycle of ATP hydrolysis and the transport pathway. [Mol Cancer Ther 2007;6(1):13–23]

Received 3/21/06; revised 10/23/06; accepted 11/17/06.

This article has been cited by other articles:

				A. L. Davidson, E. Dassa, C. Orelle, and J. Chen Structure, Function, and Evolution of Bacterial ATP-Binding Cassette Systems Microbiol. Mol. Biol. Rev., June 1, 2008; 72(2): 317 - 364. [Abstract] [Full Text] [PDF]

				K. Thamatrakoln and M. Hildebrand Silicon Uptake in Diatoms Revisited: A Model for Saturable and Nonsaturable Uptake Kinetics and the Role of Silicon Transporters Plant Physiology, March 1, 2008; 146(3): 1397 - 1407. [Abstract] [Full Text] [PDF]

				T. W. Loo, M. C. Bartlett, and D. M. Clarke Suppressor Mutations in the Transmembrane Segments of P-glycoprotein Promote Maturation of Processing Mutants and Disrupt a Subset of Drug-binding Sites J. Biol. Chem., November 2, 2007; 282(44): 32043 - 32052. [Abstract] [Full Text] [PDF]