Structure and dynamics of the drug-bound bacterial transporter EmrE in lipid bilayers

Alexander A Shcherbakov; Grant Hisao; Venkata S Mandala; Nathan E Thomas; Mohammad Soltani; E A Salter; James H Davis Jr; Katherine A Henzler-Wildman; Mei Hong

doi:10.1038/s41467-020-20468-7

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Structure and dynamics of the drug-bound bacterial transporter EmrE in lipid bilayers

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Structure and dynamics of the drug-bound bacterial transporter EmrE in lipid bilayers

Alexander A Shcherbakov, Grant Hisao, Venkata S Mandala, Nathan E Thomas, Mohammad Soltani, E A Salter, James H Davis Jr, Katherine A Henzler-Wildman and Mei Hong

Nature communications, Vol.12(1), 172

01/08/2021

DOI: 10.1038/s41467-020-20468-7

PMCID: PMC7794478

PMID: 33420032

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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 F and H solid-state NMR and a fluorinated substrate, tetra(4-fluorophenyl) phosphonium (F -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. F -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.

Anti-Bacterial Agents - chemistry

Anti-Bacterial Agents - pharmacology

Antiporters - chemistry

Antiporters - drug effects

Binding Sites

Biological Transport - drug effects

Drug Resistance, Multiple, Bacterial - drug effects

Escherichia coli - metabolism

Escherichia coli Proteins - chemistry

Escherichia coli Proteins - drug effects

Lipid Bilayers - chemistry

Membrane Transport Proteins - chemistry

Membrane Transport Proteins - drug effects

Molecular Dynamics Simulation

Protein Conformation

Details

Title: Subtitle: Structure and dynamics of the drug-bound bacterial transporter EmrE in lipid bilayers
Creators: Alexander A Shcherbakov - Massachusetts Institute of Technology
Grant Hisao - University of Wisconsin–Madison
Venkata S Mandala - Massachusetts Institute of Technology
Nathan E Thomas - University of Wisconsin–Madison
Mohammad Soltani - University of South Alabama
E A Salter - University of South Alabama
James H Davis Jr - University of South Alabama
Katherine A Henzler-Wildman - University of Wisconsin–Madison
Mei Hong - Massachusetts Institute of Technology
Resource Type: Journal article
Publication Details: Nature communications, Vol.12(1), 172
DOI: 10.1038/s41467-020-20468-7
PMID: 33420032
PMCID: PMC7794478
NLM abbreviation: Nat Commun
ISSN: 2041-1723
eISSN: 2041-1723
Grant note: R24 GM141526 / NIGMS NIH HHS P41 GM111135 / NIGMS NIH HHS S10 RR002781 / NCRR NIH HHS P41 RR002301 / NCRR NIH HHS R01 GM066976 / NIGMS NIH HHS S10 RR008438 / NCRR NIH HHS S10 RR023438 / NCRR NIH HHS R35 GM141748 / NIGMS NIH HHS R01 GM095839 / NIGMS NIH HHS S10 RR025062 / NCRR NIH HHS
Language: English
Date published: 01/08/2021
Academic Unit: Biochemistry and Molecular Biology
Record Identifier: 9985112881702771

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