PMID:23306205
| Citation |
Doshi, R, Ali, A, Shi, W, Freeman, EV, Fagg, LA and van Veen, HW (2013) Molecular disruption of the power stroke in the ATP-binding cassette transport protein MsbA. J. Biol. Chem. 288:6801-13 |
|---|---|
| Abstract |
ATP-binding cassette transporters affect drug pharmacokinetics and are associated with inherited human diseases and impaired chemotherapeutic treatment of cancers and microbial infections. Current alternating access models for ATP-binding cassette exporter activity suggest that ATP binding at the two cytosolic nucleotide-binding domains provides a power stroke for the conformational switch of the two membrane domains from the inward-facing conformation to the outward-facing conformation. In outward-facing crystal structures of the bacterial homodimeric ATP-binding cassette transporters MsbA from gram-negative bacteria and Sav1866 from Staphylococcus aureus, two transmembrane helices (3 and 4) in the membrane domains have their cytoplasmic extensions in close proximity, forming a tetrahelix bundle interface. In biochemical experiments on MsbA from Escherichia coli, we show for the first time that a robust network of inter-monomer interactions in the tetrahelix bundle is crucial for the transmission of nucleotide-dependent conformational changes to the extracellular side of the membrane domains. Our observations are the first to suggest that modulation of tetrahelix bundle interactions in ATP-binding cassette exporters might offer a potent strategy to alter their transport activity. |
| Links |
PubMed PMC3591591 Online version:10.1074/jbc.M112.430074 |
| Keywords |
ATP-Binding Cassette Transporters/chemistry; ATP-Binding Cassette Transporters/genetics; ATP-Binding Cassette Transporters/metabolism; Adenosine Triphosphate/metabolism; Bacterial Proteins/chemistry; Bacterial Proteins/genetics; Bacterial Proteins/metabolism; Binding Sites/genetics; Biological Transport; Blotting, Western; Cell Membrane/metabolism; Crystallography, X-Ray; Escherichia coli/genetics; Escherichia coli/metabolism; Kinetics; Models, Molecular; Mutation; Protein Binding; Protein Conformation; Protein Multimerization; Protein Structure, Secondary; Protein Structure, Tertiary; Substrate Specificity |
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