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Identification de nouvelles voies d'inhibition ciblant les mouvements fonctionnels de protéines : application à la transition allostérique du récepteur nicotinique de l'acétylcholine

Abstract : The analysis of the functional motion of proteins involved in various diseases and the associated evolution of cavities and grooves offers novel strategies to identify effector molecules. This work describes the gating mechanism of a nicotinic acetylcholine receptor, the (a7)5 subtype, involved in cognitive processes and various neurological disorders. The activation mechanism has been modeled by a series of intermediate conformations linking the resting and the active states of the receptor. Our transition model correctly reproduced the known quaternary motion, the blooming and the twisting. We also developed a robust algorithm to consistently track cavities in protein dynamics. Groups of protein cavities define pockets, potential binding sites for small molecules. A practical implementation, mkgridXf, is given to automatically track and identify sites in protein trajectories. The complete mapping of cavities on the (a7)5 transition structures revealed 6 distinct sites with a volume varying significantly with the conformational state of the protein. Among them, we found the orthosteric site, the Ca2+ modulatory site and 2 previously described allosteric sites. The molecular docking of allosteric modulators along the gating transition suggested the existence of an effector transmembrane site. These results paves the way toward the design of drugs with targeted activities.
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  • HAL Id : tel-02491803, version 1

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Damien Monet. Identification de nouvelles voies d'inhibition ciblant les mouvements fonctionnels de protéines : application à la transition allostérique du récepteur nicotinique de l'acétylcholine. Bio-Informatique, Biologie Systémique [q-bio.QM]. Sorbonne Université, 2018. Français. ⟨NNT : 2018SORUS206⟩. ⟨tel-02491803⟩

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