Structural basis for the blockade of MATE multidrug efflux pumps
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.
- Rosalind Franklin Univ. of Medicine and Sciences, North Chicago, IL (United States). Dept. of Biochemistry and Molecular Biology.
- Publication Date:
- OSTI Identifier:
- Grant/Contract Number:
- Accepted Manuscript
- Journal Name:
- Nature Communications
- Additional Journal Information:
- Journal Volume: 6; Journal ID: ISSN 2041-1723
- Nature Publishing Group
- Research Org:
- Argonne National Lab. (ANL), Argonne, IL (United States)
- Sponsoring Org:
- Country of Publication:
- United States
- 59 BASIC BIOLOGICAL SCIENCES; biological sciences; biophysics; biochemistry
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