Substrate-bound and substrate-free outward-facing structures of a multidrug ABC exporter.
basic_science · Level V
Where this comes from
- Record sourced from PubMed, PMID 35080979.
- Also identified by DOI 10.1126/sciadv.abg9215 and PMC identifier 8791611.
- Licence recorded as CC BY-NC.
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Abstract
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<sup>2+</sup>-bound outward-facing conformations of the <i>Bacillus subtilis</i> (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 <i>B. subtilis</i>. 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.