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Allosteric modulation of pentameric ligand gated ion channels : from the jiggling of atoms to neuropharmacological strategies

Abstract : Pentameric ligand gated ion channels (pLGICs) are brain receptors involved in fast neurotransmission and include nAchR, GABAR, GlyR or 5HT3R. When dysfunctioning, they are involved in diseases such as Alzheimer’s and Parkinson’s. In this study we have performed molecular dynamic simulations of an eukaryotic homologue of the pLGICs (GluCl) to understand the gating mechanism of pLGICs. Thanks to the analysis of two 2.5 us long simulations in which we could capture the full closing of the receptor we described in great details a gating mechanism in two steps, first twisting then blooming, that we believe applicable to the whole pLGICs family. In a second time we used our description of the gating mechanism to perform free energy calculations along the twisting reaction coordinate, for various ligands in complex with GluCl. Doing so we could show a significant difference between IVM-bound and non-bound states and provide hints for the design of new treatments.
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Nicolas Martin. Allosteric modulation of pentameric ligand gated ion channels : from the jiggling of atoms to neuropharmacological strategies. Autre. Université de Strasbourg, 2017. Français. ⟨NNT : 2017STRAF079⟩. ⟨tel-01882106⟩

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