Substrate-bound and substrate-free outward-facing structures of a multidrug ABC exporter

Multidrug ABC transporters translocate drugs across membranes by a mechanism for which the molecular features of drug release are so far unknown. Here, we resolved three ATP-Mg -bound outward-facing conformations of the (homodimeric) BmrA by x-ray crystallography and single-particle cryo-electron mi...

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Veröffentlicht in:Science advances 2022-01, Vol.8 (4), p.eabg9215-eabg9215
Hauptverfasser: Chaptal, Vincent, Zampieri, Veronica, Wiseman, Benjamin, Orelle, Cédric, Martin, Juliette, Nguyen, Kim-Anh, Gobet, Alexia, Di Cesare, Margot, Magnard, Sandrine, Javed, Waqas, Eid, Jad, Kilburg, Arnaud, Peuchmaur, Marine, Marcoux, Julien, Monticelli, Luca, Hogbom, Martin, Schoehn, Guy, Jault, Jean-Michel, Boumendjel, Ahcène, Falson, Pierre
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Sprache:eng
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Zusammenfassung:Multidrug ABC transporters translocate drugs across membranes by a mechanism for which the molecular features of drug release are so far unknown. Here, we resolved three ATP-Mg -bound outward-facing conformations of the (homodimeric) BmrA by x-ray crystallography and single-particle cryo-electron microscopy (EM) in detergent solution, one of them with rhodamine 6G (R6G), a substrate exported by BmrA when overexpressed in . Two R6G molecules bind to the drug-binding cavity at the level of the outer leaflet, between transmembrane (TM) helices 1-2 of one monomer and TM5'-6' of the other. They induce a rearrangement of TM1-2, highlighting a local flexibility that we confirmed by hydrogen/deuterium exchange and molecular dynamics simulations. In the absence of R6G, simulations show a fast postrelease occlusion of the cavity driven by hydrophobicity, while when present, R6G can move within the cavity, maintaining it open.
ISSN:2375-2548
2375-2548
DOI:10.1126/sciadv.abg9215