Identification of Cinnamic Acid Derivatives As Novel Antagonists of the Prokaryotic Proton-Gated Ion Channel GLIC
| Autor: | Pierre-Jean Corringer, Arnaud Blondel, Claire Colas, Sandrine Delarue-Cochin, Justine Marteaux, Catherine Van Renterghem, Delphine Joseph, Thérèse E. Malliavin, Marie S. Prevost |
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| Přispěvatelé: | Récepteurs Canaux - Channel Receptors, Centre National de la Recherche Scientifique (CNRS)-Institut Pasteur [Paris], Cellule Pasteur UPMC, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut Pasteur [Paris], Chimie des Substances Naturelles, Université Paris Sud, Biomolécules : Conception, Isolement, Synthèse (BioCIS), Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université Paris-Sud - Paris 11 (UP11)-Université de Cergy Pontoise (UCP), Université Paris-Seine-Université Paris-Seine, Bioinformatique structurale - Structural Bioinformatics, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), We thank the French Ministry of Superior Education and Research for the grant to M.S.P, 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., Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut Pasteur [Paris] (IP), Université Paris-Sud - Paris 11 (UP11)-Université de Cergy Pontoise (UCP), Université Paris-Seine-Université Paris-Seine-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS) |
| Rok vydání: | 2013 |
| Předmět: |
Models
Molecular MESH: Hydrogen-Ion Concentration Patch-Clamp Techniques Databases Factual Xenopus 01 natural sciences Drug Discovery MESH: Animals MESH: Xenopus MESH: Bacterial Proteins 0303 health sciences MESH: Protein Multimerization Chemistry Stereoisomerism MESH: Cyanobacteria Hydrogen-Ion Concentration Ligand (biochemistry) Transmembrane protein MESH: Ligand-Gated Ion Channels Molecular Medicine Ligand-gated ion channel Female Protons Signal transduction MESH: Models Molecular MESH: Caffeic Acids Stereochemistry GLIC Cyanobacteria MESH: Oocytes 03 medical and health sciences Caffeic Acids Bacterial Proteins MESH: Computer Simulation MESH: Patch-Clamp Techniques Animals Computer Simulation [SDV.BBM]Life Sciences [q-bio]/Biochemistry Molecular Biology Binding site 030304 developmental biology Binding Sites 010405 organic chemistry [SCCO.NEUR]Cognitive science/Neuroscience Gated Ion Channel Mutagenesis Ligand-Gated Ion Channels MESH: Stereoisomerism MESH: Databases Factual 0104 chemical sciences MESH: Cinnamates MESH: Binding Sites Cinnamates Oocytes MESH: Protons Protein Multimerization MESH: Female |
| Zdroj: | Journal of Medicinal Chemistry Journal of Medicinal Chemistry, American Chemical Society, 2013, 56 (11), pp.4619-4630. ⟨10.1021/jm400374q⟩ Journal of Medicinal Chemistry, 2013, 56 (11), pp.4619-4630. ⟨10.1021/jm400374q⟩ |
| ISSN: | 1520-4804 0022-2623 |
| DOI: | 10.1021/jm400374q |
| Popis: | International audience; 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. |
| Databáze: | OpenAIRE |
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