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Structural basis for the blockade of MATE multidrug efflux pumps

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  • Martha Radchenko

    (Rosalind Franklin University of Medicine and Science)

  • Jindrich Symersky

    (Rosalind Franklin University of Medicine and Science)

  • Rongxin Nie

    (Rosalind Franklin University of Medicine and Science)

  • Min Lu

    (Rosalind Franklin University of Medicine and Science)

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.

Suggested Citation

  • Martha Radchenko & Jindrich Symersky & Rongxin Nie & Min Lu, 2015. "Structural basis for the blockade of MATE multidrug efflux pumps," Nature Communications, Nature, vol. 6(1), pages 1-11, November.
    • Handle: RePEc:nat:natcom:v:6:y:2015:i:1:d:10.1038_ncomms8995
    DOI: 10.1038/ncomms8995
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    Cited by:

    1. Jianping Li & Yan Li & Akiko Koide & Huihui Kuang & Victor J. Torres & Shohei Koide & Da-Neng Wang & Nathaniel J. Traaseth, 2024. "Proton-coupled transport mechanism of the efflux pump NorA," Nature Communications, Nature, vol. 15(1), pages 1-12, December.

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