title: Structural insights into H+-coupled multidrug extrusion by a MATE transporter.
abstract: Multidrug and toxic compound extrusion (MATE) transporters contribute to multidrug resistance by coupling the efflux of drugs to the influx of Na(+) or H(+). Known structures of Na(+)-coupled, extracellular-facing MATE transporters from the NorM subfamily revealed 12 membrane-spanning segments related by a quasi-two-fold rotational symmetry and a multidrug-binding cavity situated near the membrane surface. Here we report the crystal structure of an H(+)-coupled MATE transporter from Bacillus halodurans and the DinF subfamily at 3.2-Å resolution, unveiling a surprisingly asymmetric arrangement of 12 transmembrane helices. We also identified a membrane-embedded substrate-binding chamber by combining crystallographic and biochemical analyses. Our studies further suggested a direct competition between H(+) and substrate during DinF-mediated transport and implied how a MATE transporter alternates between its extracellular- and intracellular-facing conformations to propel multidrug extrusion. Collectively, our results demonstrated heretofore-unrecognized mechanistic diversity among MATE transporters.
authors.affiliation: Department of Biochemistry and Molecular Biology, Rosalind Franklin University of Medicine and Science, North Chicago, Illinois, USA.
authors.forename: Min
authors.initials: M
authors.lastname: Lu
authors.forename: Martha
authors.initials: M
authors.lastname: Radchenko
authors.forename: Jindrich
authors.initials: J
authors.lastname: Symersky
authors.forename: Rongxin
authors.initials: R
authors.lastname: Nie
authors.forename: Yi
authors.initials: Y
authors.lastname: Guo
mesh_terms: D000900:Anti-Bacterial Agents / Q000378:metabolism*; D001407:Bacillus / Q000737:chemistry* / Q000201:enzymology*; D018360:Crystallography, X-Ray; D006859:Hydrogen / Q000378:metabolism*; D008954:Models, Biological; D008958:Models, Molecular; D027701:Organic Cation Transport Proteins / Q000737:chemistry* / Q000378:metabolism*; D011487:Protein Conformation
chemical_list: D000900:Anti-Bacterial Agents; D027701:Organic Cation Transport Proteins; D006859:Hydrogen