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Illumination of a progressive allosteric mechanism mediating the glycine receptor activation

Author

Listed:
  • Sophie Shi

    (Université Paris Cité, CNRS UMR 3571, Channel-Receptors Unit
    Sorbonne Université, Collège doctoral)

  • Solène N. Lefebvre

    (Université Paris Cité, CNRS UMR 3571, Channel-Receptors Unit
    Sorbonne Université, Collège doctoral)

  • Laurie Peverini

    (Université Paris Cité, CNRS UMR 3571, Channel-Receptors Unit)

  • Adrien H. Cerdan

    (Institut de Chimie de Strasbourg, UMR7177, CNRS, Université de Strasbourg)

  • Paula Milán Rodríguez

    (Université Paris Cité, CNRS UMR 3571, Channel-Receptors Unit
    Institut de Chimie de Strasbourg, UMR7177, CNRS, Université de Strasbourg)

  • Marc Gielen

    (Université Paris Cité, CNRS UMR 3571, Channel-Receptors Unit
    Sorbonne Université)

  • Jean-Pierre Changeux

    (Institut Pasteur, Collège de France)

  • Marco Cecchini

    (Institut de Chimie de Strasbourg, UMR7177, CNRS, Université de Strasbourg)

  • Pierre-Jean Corringer

    (Université Paris Cité, CNRS UMR 3571, Channel-Receptors Unit)

Abstract

Pentameric ligand-gated ion channel mediate signal transduction at chemical synapses by transiting between resting and open states upon neurotransmitter binding. Here, we investigate the gating mechanism of the glycine receptor fluorescently labeled at the extracellular-transmembrane interface by voltage-clamp fluorometry (VCF). Fluorescence reports a glycine-elicited conformational change that precedes pore opening. Low concentrations of glycine, partial agonists or specific mixtures of glycine and strychnine trigger the full fluorescence signal while weakly activating the channel. Molecular dynamic simulations of a partial agonist bound-closed Cryo-EM structure show a highly dynamic nature: a marked structural flexibility at both the extracellular-transmembrane interface and the orthosteric site, generating docking properties that recapitulate VCF data. This work illuminates a progressive propagating transition towards channel opening, highlighting structural plasticity within the mechanism of action of allosteric effectors.

Suggested Citation

  • Sophie Shi & Solène N. Lefebvre & Laurie Peverini & Adrien H. Cerdan & Paula Milán Rodríguez & Marc Gielen & Jean-Pierre Changeux & Marco Cecchini & Pierre-Jean Corringer, 2023. "Illumination of a progressive allosteric mechanism mediating the glycine receptor activation," Nature Communications, Nature, vol. 14(1), pages 1-13, December.
    • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-36471-7
    DOI: 10.1038/s41467-023-36471-7
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    References listed on IDEAS

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