Structure and dynamics of the drug-bound bacterial transporter EmrE in lipid bilayers
Name
s41467-020-20468-7.pdf
Description
Published version
Size
2.42 MB
Format
Adobe PDF
Checksum (MD5)
025e14f84ef18184d5d5be1f2e254e9a
Author(s)
Shcherbakov, Alexander Aleksandrovich
Hisao, G
Mandala, Venkata Shiva
Thomas, NE
Soltani, M
Salter, EA
Davis, JH
Henzler-Wildman, KA
Hong, Mei
Date Issued
January 2021
Journal
Nature Communications
Publisher
Springer Science and Business Media LLC
Citation
Shcherbakov, Alexander A. et al. "Structure and dynamics of the drug-bound bacterial transporter EmrE in lipid bilayers." Nature Communications 12, 1 (January 2021): 172 © 2021 The Author(s)
Version
Final published version
Abstract
The dimeric transporter, EmrE, effluxes polyaromatic cationic drugs in a proton-coupled manner to confer multidrug resistance in bacteria. Although the protein is known to adopt an antiparallel asymmetric topology, its high-resolution drug-bound structure is so far unknown, limiting our understanding of the molecular basis of promiscuous transport. Here we report an experimental structure of drug-bound EmrE in phospholipid bilayers, determined using 19F and 1H solid-state NMR and a fluorinated substrate, tetra(4-fluorophenyl) phosphonium (F4-TPP+). The drug-binding site, constrained by 214 protein-substrate distances, is dominated by aromatic residues such as W63 and Y60, but is sufficiently spacious for the tetrahedral drug to reorient at physiological temperature. F4-TPP+ lies closer to the proton-binding residue E14 in subunit A than in subunit B, explaining the asymmetric protonation of the protein. The structure gives insight into the molecular mechanism of multidrug recognition by EmrE and establishes the basis for future design of substrate inhibitors to combat antibiotic resistance.
MIT Department
Massachusetts Institute of Technology. Department of Chemistry
Terms of Use
Creative Commons Attribution-NonCommercial-NoDerivs License
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DOI of Published Version
https://doi.org/10.1038/s41467-020-20468-7
