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

Author

Listed:
  • Alexander A. Shcherbakov

    (Massachusetts Institute of Technology)

  • Grant Hisao

    (University of Wisconsin at Madison)

  • Venkata S. Mandala

    (Massachusetts Institute of Technology)

  • Nathan E. Thomas

    (University of Wisconsin at Madison)

  • Mohammad Soltani

    (University of South Alabama)

  • E. A. Salter

    (University of South Alabama)

  • James H. Davis

    (University of South Alabama)

  • Katherine A. Henzler-Wildman

    (University of Wisconsin at Madison)

  • Mei Hong

    (Massachusetts Institute of Technology)

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.

Suggested Citation

  • Alexander A. Shcherbakov & Grant Hisao & Venkata S. Mandala & Nathan E. Thomas & Mohammad Soltani & E. A. Salter & James H. Davis & Katherine A. Henzler-Wildman & Mei Hong, 2021. "Structure and dynamics of the drug-bound bacterial transporter EmrE in lipid bilayers," Nature Communications, Nature, vol. 12(1), pages 1-13, December.
  • Handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-020-20468-7
    DOI: 10.1038/s41467-020-20468-7
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    Cited by:

    1. Jianping Li & Ampon Sae Her & Alida Besch & Belen Ramirez-Cordero & Maureen Crames & James R. Banigan & Casey Mueller & William M. Marsiglia & Yingkai Zhang & Nathaniel J. Traaseth, 2024. "Dynamics underlie the drug recognition mechanism by the efflux transporter EmrE," Nature Communications, Nature, vol. 15(1), pages 1-14, December.
    2. Peyton J. Spreacker & Nathan E. Thomas & Will F. Beeninga & Merissa Brousseau & Colin J. Porter & Kylie M. Hibbs & Katherine A. Henzler-Wildman, 2022. "Activating alternative transport modes in a multidrug resistance efflux pump to confer chemical susceptibility," Nature Communications, Nature, vol. 13(1), pages 1-12, December.
    3. Alexander A. Shcherbakov & Peyton J. Spreacker & Aurelio J. Dregni & Katherine A. Henzler-Wildman & Mei Hong, 2022. "High-pH structure of EmrE reveals the mechanism of proton-coupled substrate transport," Nature Communications, Nature, vol. 13(1), pages 1-14, December.

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