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 |
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Format: | Artikel |
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. |
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ISSN: | 2375-2548 2375-2548 |
DOI: | 10.1126/sciadv.abg9215 |