%0 Journal Article %T Illumination of a progressive allosteric mechanism mediating the glycine receptor activation %+ Récepteurs Canaux - Channel Receptors %+ Collège Doctoral %+ Institut de Chimie de Strasbourg %+ Sorbonne Université (SU) %+ Département de Neuroscience - Department of Neuroscience %+ Collège de France (CdF (institution)) %A Shi, Sophie %A Lefebvre, Solène, N %A Peverini, Laurie %A Cerdan, Adrien %A Milán Rodríguez, Paula %A Gielen, Marc %A Changeux, Jean-Pierre %A Cecchini, Marco %A Corringer, Pierre-Jean %Z The work was supported by the ERC (Grant no. 788974, Dynacotine), by the “Agence Nationale de la Recherche” (Grant ANR-18-CE11-0015-01, Pentacontrol), Specific Grant Agreement No. 945539 (Human Brain Project SGA3), the doctoral school ED3C and the Foundation pour la Recherche Médicale (to Solène N. Lefebvre). %< avec comité de lecture %@ 2041-1723 %J Nature Communications %I Nature Publishing Group %V 14 %N 1 %P 795 %8 2023-02-13 %D 2023 %R 10.1038/s41467-023-36471-7 %M 36781912 %Z Life Sciences [q-bio]/Biochemistry, Molecular Biology/BiophysicsJournal articles %X Pentameric ligand-gated ion channel mediate signal transduction at chemical synapses by transiting between resting and open states upon neurotransmitter binding. Here, we investigate the gating mechanism of the glycine receptor fluorescently labeled at the extracellulartransmembrane interface by voltage-clamp fluorimetry (VCF). Fluorescence reports a glycineelicited conformational change that precedes pore opening. Low concentrations of glycine, partial agonists or specific mixtures of glycine and strychnine trigger the full fluorescence signal while weakly activating the channel. Molecular dynamic simulations of a partial agonist boundclosed Cryo-EM structure show a highly dynamic nature: a marked structural flexibility at both the extracellular-transmembrane interface and the orthosteric site, generating docking properties that recapitulate VCF data. This work thus illuminates a progressive propagating transition towards channel opening, displaying structural plasticity with novel implications concerning the mechanism of action of allosteric effectors. %G English %2 https://pasteur.hal.science/pasteur-03993599v1/document %2 https://pasteur.hal.science/pasteur-03993599v1/file/2022-Shi.pdf %L pasteur-03993599 %U https://pasteur.hal.science/pasteur-03993599