title: Structural basis for the blockade of MATE multidrug efflux pumps.
abstract: Multidrug and toxic compound extrusion (MATE) transporters underpin multidrug resistance by using the H(+) or Na(+) electrochemical gradient to extrude different drugs across cell membranes. MATE transporters can be further parsed into the DinF, NorM and eukaryotic subfamilies based on their amino-acid sequence similarity. Here we report the 3.0 Å resolution X-ray structures of a protonation-mimetic mutant of an H(+)-coupled DinF transporter, as well as of an H(+)-coupled DinF and a Na(+)-coupled NorM transporters in complexes with verapamil, a small-molecule pharmaceutical that inhibits MATE-mediated multidrug extrusion. Combining structure-inspired mutational and functional studies, we confirm the biological relevance of our crystal structures, reveal the mechanistic differences among MATE transporters, and suggest how verapamil inhibits MATE-mediated multidrug efflux. Our findings offer insights into how MATE transporters extrude chemically and structurally dissimilar drugs and could inform the design of new strategies for tackling multidrug resistance.
authors.affiliation: Department of Biochemistry and Molecular Biology, Rosalind Franklin University of Medicine and Science, 3333 Green Bay Road, North Chicago, Illinois 60064, USA.
authors.forename: Martha
authors.initials: M
authors.lastname: Radchenko
authors.affiliation: Department of Biochemistry and Molecular Biology, Rosalind Franklin University of Medicine and Science, 3333 Green Bay Road, North Chicago, Illinois 60064, USA.
authors.forename: Jindrich
authors.initials: J
authors.lastname: Symersky
authors.affiliation: Department of Biochemistry and Molecular Biology, Rosalind Franklin University of Medicine and Science, 3333 Green Bay Road, North Chicago, Illinois 60064, USA.
authors.forename: Rongxin
authors.initials: R
authors.lastname: Nie
authors.affiliation: Department of Biochemistry and Molecular Biology, Rosalind Franklin University of Medicine and Science, 3333 Green Bay Road, North Chicago, Illinois 60064, USA.
authors.forename: Min
authors.initials: M
authors.lastname: Lu
mesh_terms: D001665:Binding Sites; D004926:Escherichia coli; D029968:Escherichia coli Proteins / Q000037:antagonists & inhibitors; D008024:Ligands; D008968:Molecular Conformation; D027701:Organic Cation Transport Proteins / Q000037:antagonists & inhibitors* / Q000187:drug effects / Q000235:genetics; D014700:Verapamil / Q000494:pharmacology*
chemical_list: C574042:DinF protein, E coli; D029968:Escherichia coli Proteins; D008024:Ligands; D027701:Organic Cation Transport Proteins; D014700:Verapamil