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

Autor: Olofsson L; 1] CNRS UMR5048, Centre de Biochimie Structurale, 29 rue de Navacelles, 34090 Montpellier, France [2] INSERM U1054, 34090 Montpellier, France [3] Universités Montpellier I et II, 34090 Montpellier, France., Felekyan S; Lehrstuhl für Molekulare Physikalische Chemie, Heinrich-Heine-Universität, 40225 Düsseldorf, Germany., Doumazane E; 1] Universités Montpellier I et II, 34090 Montpellier, France [2] UMR 5203 CNRS, Institut de Génomique Fonctionnelle, 34090 Montpellier, France [3] U661 INSERM, 34090 Montpellier, France., Scholler P; 1] Universités Montpellier I et II, 34090 Montpellier, France [2] UMR 5203 CNRS, Institut de Génomique Fonctionnelle, 34090 Montpellier, France [3] U661 INSERM, 34090 Montpellier, France [4] Cisbio Bioassays, 30200 Codolet, France., Fabre L; 1] Universités Montpellier I et II, 34090 Montpellier, France [2] UMR 5203 CNRS, Institut de Génomique Fonctionnelle, 34090 Montpellier, France [3] U661 INSERM, 34090 Montpellier, France [4] Cisbio Bioassays, 30200 Codolet, France., Zwier JM; Cisbio Bioassays, 30200 Codolet, France., Rondard P; 1] Universités Montpellier I et II, 34090 Montpellier, France [2] UMR 5203 CNRS, Institut de Génomique Fonctionnelle, 34090 Montpellier, France [3] U661 INSERM, 34090 Montpellier, France., Seidel CA; Lehrstuhl für Molekulare Physikalische Chemie, Heinrich-Heine-Universität, 40225 Düsseldorf, Germany., Pin JP; 1] Universités Montpellier I et II, 34090 Montpellier, France [2] UMR 5203 CNRS, Institut de Génomique Fonctionnelle, 34090 Montpellier, France [3] U661 INSERM, 34090 Montpellier, France., Margeat E; 1] CNRS UMR5048, Centre de Biochimie Structurale, 29 rue de Navacelles, 34090 Montpellier, France [2] INSERM U1054, 34090 Montpellier, France [3] Universités Montpellier I et II, 34090 Montpellier, France.
Jazyk: angličtina
Zdroj: Nature communications [Nat Commun] 2014 Oct 17; Vol. 5, pp. 5206. Date of Electronic Publication: 2014 Oct 17.
DOI: 10.1038/ncomms6206
Abstrakt: 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.
Databáze: MEDLINE
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