Journal
BIOCHIMICA ET BIOPHYSICA ACTA-PROTEINS AND PROTEOMICS
Volume 1794, Issue 5, Pages 725-737Publisher
ELSEVIER
DOI: 10.1016/j.bbapap.2008.12.004
Keywords
ATP-binding cassette transporter; Catalytic cycle; Energy-coupling; Multidrug binding and translocation; Structure-function relationships
Categories
Funding
- Biotechnology and Biological Sciences Research Council (BBSRC)
- Medical Research Council (MRC)
- Swiss National Foundation
- Novartis Foundation
- European Molecular Biology Organization (EMBO)
- BBSRC [BB/F008333/1] Funding Source: UKRI
- MRC [G0401165] Funding Source: UKRI
- Biotechnology and Biological Sciences Research Council [BB/F008333/1] Funding Source: researchfish
- Medical Research Council [G0401165] Funding Source: researchfish
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Multidrug ABC transporters such as the human multidrug resistance P-glycoprotein (ABCB1)play an important role in the extrusion of drugs from the cell and their overexpression can be a cause of failure of anticancer and antimicrobial chemotherapy. These transport systems contain two nucleotide-binding domains (NBDs) where ATP is bound and hydrolyzed and two membrane domains (MDs) which mediate vectorial transport of substrates across the cell membrane. Recent crystal structures of the bacterial ABCB1 homologues Sav1866 from Staphylococcus aureus and MsbA from Salmonella typhimurium and other organisms shed light on the possible conformational states adopted by multidrug ABC transporters during transport. These structures help to interpret cellular and biochemical data gathered on these transport proteins over the past three decades. However, there are contradictory views on how the catalytic cycle of ATP binding and hydrolysis by the NBDs is linked to the change in drug binding affinity at the MDs, which underlies the capture (high affinity) of the transported drug on one side of the membrane and its release (low affinity) on the other. This review provides an overview of the current evidence for the different transport models and establishes the most recent structure-function relationships in multidrug ABC transporters. (C) 2008 Elsevier B.V. All rights reserved.
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