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Applications de la fluorescence pour la caractérisation structurale et dynamique d'intermédiaires conformationnels des récepteurs-canaux pentamériques

Abstract : Pentameric ligand-gated ion channels (pLGICs) are membrane proteins found in both eukaryotes such as the glycine and serotonin receptors and in some prokaryotes like GLIC. In Humans, these receptors are involved in fast synaptic transmission and are a major therapeutic target for general anesthetics or anxiolytics and their mutation lead to severe diseases such as myasthenia, epilepsies or rare neurological diseases like hyperekplexia. Agonist binding on these receptors promote structural reorganizations leading to the active state with an open pore allowing ion flux. Structural and functional properties of these receptors have been studied and combined in this work to explore conformational dynamics of pLGICs. Several approaches have been used to: 1) determine pre-activation kinetics of GLIC at the hundreds of milliseconds timescale, 2) measure the effect of mutations deeply impacting global reorganizations highlighting the major role of allosteric coupling of different protein domains to permit its activation, 3) characterize intermediate states of eukaryotic pLGICs upstream activation. Combined to structural analysis, fluorescence data obtained provide detailed description of conformational intermediates of pLGICs activation and deepen the knowledge of molecular mechanisms determining normal and pathological functioning of these receptors.
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Submitted on : Sunday, November 29, 2020 - 7:26:30 PM
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  • HAL Id : tel-03030123, version 1

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Solène Lefebvre. Applications de la fluorescence pour la caractérisation structurale et dynamique d'intermédiaires conformationnels des récepteurs-canaux pentamériques. Biophysique. Sorbonne Université, 2019. Français. ⟨NNT : 2019SORUS207⟩. ⟨tel-03030123⟩

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