%0 Journal Article %T Identification of Cinnamic Acid Derivatives As Novel Antagonists of the Prokaryotic Proton-Gated Ion Channel GLIC %+ Récepteurs Canaux - Channel Receptors %+ Cellule Pasteur UPMC %+ Chimie des Substances Naturelles %+ Biomolécules : Conception, Isolement, Synthèse (BioCIS) %+ Bioinformatique structurale - Structural Bioinformatics %A Prevost, Marie, S. %A Delarue-Cochin, Sandrine %A Marteaux, Justine %A Colas, Claire %A van Renterghem, Catherine %A Blondel, Arnaud %A Malliavin, Thérèse %A Corringer, Pierre-Jean %A Joseph, Delphine %Z We thank the French Ministry of Superior Education and Research for the grant to M.S.P %< avec comité de lecture %@ 0022-2623 %J Journal of Medicinal Chemistry %I American Chemical Society %V 56 %N 11 %P 4619 - 4630 %8 2013-06-04 %D 2013 %R 10.1021/jm400374q %M 23682762 %Z Cognitive science/Neuroscience %Z Life Sciences [q-bio]/Biochemistry, Molecular BiologyJournal articles %X Pentameric ligand gated ion channels (pLGICs) mediate signal transduction. The binding of an extracellular ligand is coupled to the transmembrane channel opening. So far, all known agonists bind at the interface between subunits in a topologically conserved "orthosteric site" whose amino acid composition defines the pharmacological specificity of pLGIC subtypes. A striking exception is the bacterial proton-activated GLIC protein, exhibiting an uncommon orthosteric binding site in terms of sequence and local architecture. Among a library of Gloeobacter violaceus metabolites, we identified a series of cinnamic acid derivatives, which antagonize the GLIC proton-elicited response. Structure-activity analysis shows a key contribution of the carboxylate moiety to GLIC inhibition. Molecular docking coupled to site-directed mutagenesis support that the binding pocket is located below the classical orthosteric site. These antagonists provide new tools to modulate conformation of GLIC, currently used as a prototypic pLGIC, and opens new avenues to study the signal transduction mechanism. %G English %Z We are indebted to M. Delarue and L. Sauguet for the gift of the 2.4 Å GLIC structure before its publication for the a posteriori docking and, together with F. Poitevin, for helpful comments. We are grateful to K. Leblanc for HPLC analyses and mass measurements. %2 https://pasteur.hal.science/pasteur-01721702/document %2 https://pasteur.hal.science/pasteur-01721702/file/Identification%20of%20Cinnamic%20Acid%20Derivatives.pdf %L pasteur-01721702 %U https://pasteur.hal.science/pasteur-01721702 %~ PASTEUR %~ UPMC %~ CNRS %~ UNIV-CERGY %~ UNIV-PSUD %~ INC-CNRS %~ UNIV-PARIS-SACLAY %~ UNIV-PSUD-SACLAY %~ SORBONNE-UNIVERSITE %~ SU-MEDECINE %~ SU-MED %~ BIOCIS %~ SU-TI %~ GS-HEALTH-DRUG-SCIENCES %~ ALLIANCE-SU %~ TEST2-HALCNRS %~ CHAN-RECEPTORS %~ PASTEUR_UMR3571