Structural basis for the blockade of MATE multidrug efflux pumps.

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Radchenko M, Symersky J, Nie R, Lu M

Structural basis for the blockade of MATE multidrug efflux pumps.

Nat Commun. 2015 Aug 6;6:7995. doi: 10.1038/ncomms8995.

PubMed ID

26246409 [ View in PubMed

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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 A 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.

DrugBank Data that Cites this Article

Drug Transporters

Drug	Transporter	Kind	Organism	Pharmacological Action	Actions
Verapamil	Multidrug and toxin extrusion protein 1	Protein	Humans	Unknown	Inhibitor	Details
Verapamil	Multidrug and toxin extrusion protein 2	Protein	Humans	Unknown	Inhibitor	Details