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Allosteric modulators enhance agonist efficacy by increasing the residence time of a GPCR in the active state

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  • Anne-Marinette Cao

    (Centre de Biologie Structurale (CBS), Univ. Montpellier, CNRS, INSERM
    École Polytechnique Fédérale de Lausanne (EPFL), SB ISIC LCBM)

  • Robert B. Quast

    (Centre de Biologie Structurale (CBS), Univ. Montpellier, CNRS, INSERM)

  • Fataneh Fatemi

    (Centre de Biologie Structurale (CBS), Univ. Montpellier, CNRS, INSERM
    Protein Research Center, Shahid Beheshti University)

  • Philippe Rondard

    (Institut de Génomique Fonctionnelle, Univ. Montpellier, CNRS, INSERM)

  • Jean-Philippe Pin

    (Institut de Génomique Fonctionnelle, Univ. Montpellier, CNRS, INSERM)

  • Emmanuel Margeat

    (Centre de Biologie Structurale (CBS), Univ. Montpellier, CNRS, INSERM)

Abstract

Much hope in drug development comes from the discovery of positive allosteric modulators (PAM) that display target subtype selectivity and act by increasing agonist potency and efficacy. How such compounds can allosterically influence agonist action remains unclear. Metabotropic glutamate receptors (mGlu) are G protein-coupled receptors that represent promising targets for brain diseases, and for which PAMs acting in the transmembrane domain have been developed. Here, we explore the effect of a PAM on the structural dynamics of mGlu2 in optimized detergent micelles using single molecule FRET at submillisecond timescales. We show that glutamate only partially stabilizes the extracellular domains in the active state. Full activation is only observed in the presence of a PAM or the Gi protein. Our results provide important insights on the role of allosteric modulators in mGlu activation, by stabilizing the active state of a receptor that is otherwise rapidly oscillating between active and inactive states.

Suggested Citation

  • Anne-Marinette Cao & Robert B. Quast & Fataneh Fatemi & Philippe Rondard & Jean-Philippe Pin & Emmanuel Margeat, 2021. "Allosteric modulators enhance agonist efficacy by increasing the residence time of a GPCR in the active state," Nature Communications, Nature, vol. 12(1), pages 1-13, December.
    • Handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-25620-5
    DOI: 10.1038/s41467-021-25620-5
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    Cited by:

    1. Mingyu Li & Xiaobing Lan & Xinchao Shi & Chunhao Zhu & Xun Lu & Jun Pu & Shaoyong Lu & Jian Zhang, 2024. "Delineating the stepwise millisecond allosteric activation mechanism of the class C GPCR dimer mGlu5," Nature Communications, Nature, vol. 15(1), pages 1-14, December.

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