1. Neuroscience
  2. Structural Biology and Molecular Biophysics

Modulation of the Erwinia ligand-gated ion channel (ELIC) and the 5-HT3 receptor via a common vestibule site

  1. Marijke Brams
  2. Cedric Govaerts
  3. Kumiko Kambara
  4. Kerry L Price
  5. Radovan Spurny
  6. Anant Gharpure
  7. Els Pardon
  8. Genevieve L Evans
  9. Daniel Bertrand
  10. Sarah CR Lummis
  11. Ryan E Hibbs
  12. Jan Steyaert
  13. Chris Ulens  Is a corresponding author
  1. KU Leuven, Belgium
  2. Université libre de Bruxelles, Belgium
  3. HiQScreen, Switzerland
  4. University of Cambridge, United Kingdom
  5. University of Texas Southwestern Medical Center, United States
  6. VIB-VUB, Belgium
https://doi.org/10.7554/eLife.51511
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Cite this article
  1. Marijke Brams
  2. Cedric Govaerts
  3. Kumiko Kambara
  4. Kerry L Price
  5. Radovan Spurny
  6. Anant Gharpure
  7. Els Pardon
  8. Genevieve L Evans
  9. Daniel Bertrand
  10. Sarah CR Lummis
  11. Ryan E Hibbs
  12. Jan Steyaert
  13. Chris Ulens
(2020)
Modulation of the Erwinia ligand-gated ion channel (ELIC) and the 5-HT3 receptor via a common vestibule site
eLife 9:e51511.
https://doi.org/10.7554/eLife.51511
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Abstract

Pentameric ligand-gated ion channels (pLGICs) or Cys-loop receptors are involved in fast synaptic signaling in the nervous system. Allosteric modulators bind to sites that are remote from the neurotransmitter binding site, but modify coupling of ligand binding to channel opening. In this study, we developed nanobodies (single domain antibodies), which are functionally active as allosteric modulators, and solved co-crystal structures of the prokaryote (Erwinia) channel ELIC bound either to a positive or a negative allosteric modulator. The allosteric nanobody binding sites partially overlap with those of small molecule modulators, including a vestibule binding site that is not accessible in some pLGICs. Using mutagenesis, we extrapolate the functional importance of the vestibule binding site to the human 5-HT3 receptor, suggesting a common mechanism of modulation in this protein and ELIC. Thus we identify key elements of allosteric binding sites, and extend drug design possibilities in pLGICs with an accessible vestibule site.

Data availability

Atomic coordinates and structure factors have been deposited with the Protein Data Bank under accession numbers 6SSI for the ELIC+PAM-Nb structure and 6SSP for the ELIC+NAM-Nb structure. The raw X-ray diffraction images for both data sets have been deposited on datadryad.org under accession number doi:10.5061/dryad.pv4097s.

The following data sets were generated

Article and author information

Author details

  1. Marijke Brams

    Department of Cellular and Molecular Medicine, KU Leuven, Leuven, Belgium
    Competing interests
    The authors declare that no competing interests exist.

  2. Cedric Govaerts

    Laboratory for the Structure and Function of Biological Membranes, Université libre de Bruxelles, Brussels, Belgium
    Competing interests
    The authors declare that no competing interests exist.

  3. Kumiko Kambara

    HiQScreen, Geneva, Switzerland
    Competing interests
    The authors declare that no competing interests exist.

  4. Kerry L Price

    Department of Biochemistry, University of Cambridge, Cambridge, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.

  5. Radovan Spurny

    Department of Cellular and Molecular Medicine, KU Leuven, Leuven, Belgium
    Competing interests
    The authors declare that no competing interests exist.

  6. Anant Gharpure

    Department of Neuroscience, University of Texas Southwestern Medical Center, Dallas, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-4458-359X

  7. Els Pardon

    Center for Structural Biology, VIB-VUB, Brussels, Belgium
    Competing interests
    The authors declare that no competing interests exist.

  8. Genevieve L Evans

    Department of Cellular and Molecular Medicine, KU Leuven, Leuven, Belgium
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-8612-9539

  9. Daniel Bertrand

    HiQScreen, Geneva, Switzerland
    Competing interests
    The authors declare that no competing interests exist.

  10. Sarah CR Lummis

    Department of Biochemistry, University of Cambridge, Cambridge, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.

  11. Ryan E Hibbs

    Department of Neuroscience, University of Texas Southwestern Medical Center, Dallas, United States
    Competing interests
    The authors declare that no competing interests exist.

  12. Jan Steyaert

    Center for Structural Biology, VIB-VUB, Brussels, Belgium
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-3825-874X

  13. Chris Ulens

    Department of Cellular and Molecular Medicine, KU Leuven, Leuven, Belgium
    For correspondence
    chris.ulens@kuleuven.be
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-8202-5281

Funding

SBO/IWT (1200261)

  • Jan Steyaert
  • Chris Ulens

FWO-Vlaanderen (G.0762.13)

  • Jan Steyaert
  • Chris Ulens

KU Leuven (OT/13/095)

  • Chris Ulens

KU Leuven (C32/16/035)

  • Chris Ulens

KU Leuven (C14/17/093)

  • Chris Ulens

INSTRUCT-ERIC

  • Jan Steyaert

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Reviewing Editor

  1. Cynthia M Czajkowski, University of Wisconsin, Madison, United States

Version history

  1. Received: August 30, 2019
  2. Accepted: January 27, 2020
  3. Accepted Manuscript published: January 28, 2020 (version 1)
  4. Version of Record published: February 12, 2020 (version 2)

Copyright

© 2020, Brams et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Marijke Brams
  2. Cedric Govaerts
  3. Kumiko Kambara
  4. Kerry L Price
  5. Radovan Spurny
  6. Anant Gharpure
  7. Els Pardon
  8. Genevieve L Evans
  9. Daniel Bertrand
  10. Sarah CR Lummis
  11. Ryan E Hibbs
  12. Jan Steyaert
  13. Chris Ulens
(2020)
Modulation of the Erwinia ligand-gated ion channel (ELIC) and the 5-HT3 receptor via a common vestibule site
eLife 9:e51511.
https://doi.org/10.7554/eLife.51511

Share this article

https://doi.org/10.7554/eLife.51511

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