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Illumination of a progressive allosteric mechanism mediating the glycine receptor activation
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Edité par CCSD ; Nature Publishing Group -
International audience. 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.
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