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:
-
- Rosalind Franklin Univ. of Medicine and Sciences, North Chicago, IL (United States). Dept. of Biochemistry and Molecular Biology.
- Publication Date:
- Research Org.:
- Argonne National Laboratory (ANL), Argonne, IL (United States)
- Sponsoring Org.:
- USDOE
- OSTI Identifier:
- 1214707
- Grant/Contract Number:
- AC02-06CH11357
- Resource Type:
- Accepted Manuscript
- Journal Name:
- Nature Communications
- Additional Journal Information:
- Journal Volume: 6; Journal ID: ISSN 2041-1723
- Publisher:
- Nature Publishing Group
- Country of Publication:
- United States
- Language:
- English
- Subject:
- 59 BASIC BIOLOGICAL SCIENCES; biological sciences; biophysics; biochemistry
Citation Formats
Radchenko, Martha, Symersky, Jindrich, Nie, Rongxin, and Lu, Min. Structural basis for the blockade of MATE multidrug efflux pumps. United States: N. p., 2015.
Web. doi:10.1038/ncomms8995.
Radchenko, Martha, Symersky, Jindrich, Nie, Rongxin, & Lu, Min. Structural basis for the blockade of MATE multidrug efflux pumps. United States. https://doi.org/10.1038/ncomms8995
Radchenko, Martha, Symersky, Jindrich, Nie, Rongxin, and Lu, Min. Thu .
"Structural basis for the blockade of MATE multidrug efflux pumps". United States. https://doi.org/10.1038/ncomms8995. https://www.osti.gov/servlets/purl/1214707.
@article{osti_1214707,
title = {Structural basis for the blockade of MATE multidrug efflux pumps},
author = {Radchenko, Martha and Symersky, Jindrich and Nie, Rongxin and Lu, Min},
abstractNote = {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.},
doi = {10.1038/ncomms8995},
journal = {Nature Communications},
number = ,
volume = 6,
place = {United States},
year = {Thu Aug 06 00:00:00 EDT 2015},
month = {Thu Aug 06 00:00:00 EDT 2015}
}
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