title: Fine tuning of sub-millisecond conformational dynamics controls metabotropic glutamate receptors agonist efficacy.
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.
authors.affiliation: 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.
authors.forename: Linnea
authors.initials: L
authors.lastname: Olofsson
authors.affiliation: Lehrstuhl für Molekulare Physikalische Chemie, Heinrich-Heine-Universität, 40225 Düsseldorf, Germany.
authors.forename: Suren
authors.initials: S
authors.lastname: Felekyan
authors.affiliation: 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.
authors.forename: Etienne
authors.initials: E
authors.lastname: Doumazane
authors.affiliation: 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.
authors.forename: Pauline
authors.initials: P
authors.lastname: Scholler
authors.affiliation: 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.
authors.forename: Ludovic
authors.initials: L
authors.lastname: Fabre
authors.affiliation: Cisbio Bioassays, 30200 Codolet, France.
authors.forename: Jurriaan M
authors.initials: JM
authors.lastname: Zwier
authors.affiliation: 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.
authors.forename: Philippe
authors.initials: P
authors.lastname: Rondard
authors.affiliation: Lehrstuhl für Molekulare Physikalische Chemie, Heinrich-Heine-Universität, 40225 Düsseldorf, Germany.
authors.forename: Claus A M
authors.initials: CA
authors.lastname: Seidel
authors.affiliation: 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.
authors.forename: Jean-Philippe
authors.initials: JP
authors.lastname: Pin
authors.affiliation: 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.
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Margeat
mesh_terms: D000495:Allosteric Site; D020134:Catalytic Domain; D002450:Cell Communication; D031541:Fluorescence Resonance Energy Transfer; D006146:Guanidines / Q000737:chemistry; D057809:HEK293 Cells; D006801:Humans; D007700:Kinetics; D008024:Ligands; D008968:Molecular Conformation; D009154:Mutation; D017785:Photons; D011485:Protein Binding; D011487:Protein Conformation; D055503:Protein Multimerization; D018094:Receptors, Metabotropic Glutamate / Q000819:agonists* / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D006146:Guanidines; D008024:Ligands; D018094:Receptors, Metabotropic Glutamate; C108822:metabotropic glutamate receptor 2; C117872:benzylguanidine