This content will become publicly available on August 6, 2015
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
Enter terms in the toolbar above to search the full text of this document for pages containing specific keywords.