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This molecular mechanism of action provides an incredibly efficient efflux of a vast array of hydrophobic drugs, ensuring the survival of cancer cells despite toxic chemotherapy for reviews see 45. Based on biochemical experiments and the commonality of various mammalian and bacterial ABC transporter structures it is generally believed that the fundamental molecular mechanism of substrate transport is shared among ABC transporters 678. From bacteria to humans, ABC transporters are composed of at least two membrane-embedded transmembrane domains TMDs and two cytoplasmic nucleotide binding domains NBDs. Crystal structures of full-length ABC transporters have revealed two major conformations: Only one of two gates is open at any time: Conversely, in the outward-facing conformation the cytoplasmic gate is closed and the transported drug is free to dissociate to the extracellular compartment.
The above conformational transitions are accompanied by the switch of the affinity of the substrate binding sites from high- to low-affinity to ensure substrate transport against the concentration gradient 14 Notably, the recently solved structure of the antibacterial peptide ABC transporter McjD is occluded on both sides of the membrane. This conformation, termed nucleotide-bound outward occluded, probably represents a transition intermediate between the outward-open and inward-open TMD conformations of ABC exporters Repeated formation and disruption of the NBD dimer is generally agreed to involve the cooperative, ATP-dependent interaction of the NBDs, but because the resolved structures do not represent all phases of the transport cycle the exact sequence of events is unknown.
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