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Fine tuning of sub-millisecond conformational dynamics controls metabotropic glutamate receptors agonist efficacy

Author

Listed:
  • Linnea Olofsson

    (CNRS UMR5048, Centre de Biochimie Structurale
    INSERM U1054
    Universités Montpellier I et II)

  • Suren Felekyan

    (Lehrstuhl für Molekulare Physikalische Chemie, Heinrich-Heine-Universität)

  • Etienne Doumazane

    (Universités Montpellier I et II
    UMR 5203 CNRS, Institut de Génomique Fonctionnelle
    U661 INSERM)

  • Pauline Scholler

    (Universités Montpellier I et II
    UMR 5203 CNRS, Institut de Génomique Fonctionnelle
    U661 INSERM
    Cisbio Bioassays)

  • Ludovic Fabre

    (Universités Montpellier I et II
    UMR 5203 CNRS, Institut de Génomique Fonctionnelle
    U661 INSERM
    Cisbio Bioassays)

  • Jurriaan M. Zwier

    (Cisbio Bioassays)

  • Philippe Rondard

    (Universités Montpellier I et II
    UMR 5203 CNRS, Institut de Génomique Fonctionnelle
    U661 INSERM)

  • Claus A. M. Seidel

    (Lehrstuhl für Molekulare Physikalische Chemie, Heinrich-Heine-Universität)

  • Jean-Philippe Pin

    (Universités Montpellier I et II
    UMR 5203 CNRS, Institut de Génomique Fonctionnelle
    U661 INSERM)

  • Emmanuel Margeat

    (CNRS UMR5048, Centre de Biochimie Structurale
    INSERM U1054
    Universités Montpellier I et II)

Abstract

Efficient cell-to-cell communication relies on the accurate signalling of cell surface receptors. Understanding the molecular bases of their activation requires the characterization of the dynamic equilibrium between active and resting states. Here, we monitor, using single-molecule Förster resonance energy transfer, the kinetics of the reorientation of the extracellular ligand-binding domain of the metabotropic glutamate receptor (mGluR), a class C G-protein-coupled receptor. We demonstrate that most receptors oscillate between a resting- and an active-conformation on a sub-millisecond timescale. Interestingly, we demonstrate that differences in agonist efficacies stem from differing abilities to shift the conformational equilibrium towards the fully active state, rather than from the stabilization of alternative static conformations, which further highlights the dynamic nature of mGluRs and revises our understanding of receptor activation and allosteric modulation.

Suggested Citation

  • Linnea Olofsson & Suren Felekyan & Etienne Doumazane & Pauline Scholler & Ludovic Fabre & Jurriaan M. Zwier & Philippe Rondard & Claus A. M. Seidel & Jean-Philippe Pin & Emmanuel Margeat, 2014. "Fine tuning of sub-millisecond conformational dynamics controls metabotropic glutamate receptors agonist efficacy," Nature Communications, Nature, vol. 5(1), pages 1-12, December.
    • Handle: RePEc:nat:natcom:v:5:y:2014:i:1:d:10.1038_ncomms6206
    DOI: 10.1038/ncomms6206
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    Cited by:

    1. Chris Habrian & Naomi Latorraca & Zhu Fu & Ehud Y. Isacoff, 2023. "Homo- and hetero-dimeric subunit interactions set affinity and efficacy in metabotropic glutamate receptors," Nature Communications, Nature, vol. 14(1), pages 1-10, December.
    2. Andreas Hartmann & Koushik Sreenivasa & Mathias Schenkel & Neharika Chamachi & Philipp Schake & Georg Krainer & Michael Schlierf, 2023. "An automated single-molecule FRET platform for high-content, multiwell plate screening of biomolecular conformations and dynamics," Nature Communications, Nature, vol. 14(1), pages 1-12, December.

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