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In the assembled transporter, two composite ATP-binding active sites are formed by the interaction of each LSGGQ motif with an ATP molecule bound to the Walker A and B motifs of the opposite NBD ( 8,9).
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Its bilobal architecture consists of a catalytic core subdomain containing the Walker A (P-loop) and B consensus nucleotide-binding motifs, and a flexibly attached α-helical subdomain containing the LSGGQ ABC signature sequence ( 6).
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In contrast to the TMD, the NBD is highly conserved in sequence and structure. The TMDs form the membrane channel and contain substrate-binding sites. These domains are configured in various combinations of two transmembrane domains (TMDs) and two NBDs as four separate subunits, two half transporters, or a single polypeptide, with the canonical configuration TMD-NBD-TMD-NBD, although exceptions with the opposite order or additional N-terminal or regulatory domains also exist ( 6,7). The general architecture of ABC transporters is dimeric, with each half comprising one domain that spans the membrane and one cytosolic nucleotide-binding domain (NBD) or ABC. Members of this superfamily are involved in multidrug resistance (MDR) in both human cancers and pathogenic microbes, and significant human genetic disorders are caused by mutations in many ABC genes ( 5). ABC transporters comprise one of the largest protein superfamilies, are found in all living organisms, and transport a wide range of substrates ( 1–4). We correlate our findings with elastic network and molecular-dynamics simulation analyses of the Sav1866 NBD monomer, and with existing experimental data, to argue that the observed transition is physiological, and that the final structure observed in the ATP/apo simulations corresponds to the tight/loose state of the NBD dimer characterized experimentally.ĪTP-binding cassette (ABC) transporters use the energy of ATP hydrolysis to translocate substrates across cellular membranes, although in some atypical cases they are gated channels or transmembrane signal receptors. In two simulations of the ATP/apo state, the empty site opened substantially by way of rotation of the nucleotide-binding domain (NBD) core subdomain, whereas the ATP-bound site remained occluded and intact. Here, we report molecular-dynamics simulations of the bacterial multidrug ATP-binding cassette transporter Sav1866. Biochemical studies have characterized an occluded state of the transporter in which nucleotide is tenaciously bound in one active site, whereas the opposite active site is empty or binds nucleotide loosely. They have two transmembrane domains and two cytosolic nucleotide-binding domains. ATP-binding cassette transporters use the energy of ATP hydrolysis to transport substrates across cellular membranes.