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

Linnea Olofsson, Suren Felekyan, Etienne Doumazane, Pauline Scholler, Ludovic Fabre, Jurriaan M. Zwier, Philippe Rondard, Claus A. M. Seidel, Jean-Philippe Pin () and Emmanuel Margeat ()
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Linnea Olofsson: CNRS UMR5048, Centre de Biochimie Structurale
Suren Felekyan: Lehrstuhl für Molekulare Physikalische Chemie, Heinrich-Heine-Universität
Etienne Doumazane: Universités Montpellier I et II
Pauline Scholler: Universités Montpellier I et II
Ludovic Fabre: Universités Montpellier I et II
Jurriaan M. Zwier: Cisbio Bioassays
Philippe Rondard: Universités Montpellier I et II
Claus A. M. Seidel: Lehrstuhl für Molekulare Physikalische Chemie, Heinrich-Heine-Universität
Jean-Philippe Pin: Universités Montpellier I et II
Emmanuel Margeat: CNRS UMR5048, Centre de Biochimie Structurale

Nature Communications, 2014, vol. 5, issue 1, 1-12

Abstract: 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.

Date: 2014
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Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:5:y:2014:i:1:d:10.1038_ncomms6206

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DOI: 10.1038/ncomms6206

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