title: Identification of cinnamic acid derivatives as novel antagonists of the prokaryotic proton-gated ion channel GLIC.
abstract: 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.
authors.affiliation: Institut Pasteur, Unité Récepteurs-Canaux, Paris, France.
authors.forename: Marie S
authors.initials: MS
authors.lastname: Prevost
authors.forename: Sandrine
authors.initials: S
authors.lastname: Delarue-Cochin
authors.forename: Justine
authors.initials: J
authors.lastname: Marteaux
authors.forename: Claire
authors.initials: C
authors.lastname: Colas
authors.forename: Catherine
authors.initials: C
authors.lastname: Van Renterghem
authors.forename: Arnaud
authors.initials: A
authors.lastname: Blondel
authors.forename: Thérèse
authors.initials: T
authors.lastname: Malliavin
authors.forename: Pierre-Jean
authors.initials: PJ
authors.lastname: Corringer
authors.forename: Delphine
authors.initials: D
authors.lastname: Joseph
mesh_terms: D000818:Animals; D001426:Bacterial Proteins / Q000037:antagonists & inhibitors* / Q000502:physiology; D001665:Binding Sites; D002109:Caffeic Acids / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D002934:Cinnamates / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D003198:Computer Simulation; D000458:Cyanobacteria / Q000378:metabolism; D016208:Databases, Factual; D005260:Female; D006863:Hydrogen-Ion Concentration; D058446:Ligand-Gated Ion Channels / Q000037:antagonists & inhibitors* / Q000502:physiology; D008958:Models, Molecular; D009865:Oocytes / Q000187:drug effects / Q000502:physiology; D018408:Patch-Clamp Techniques; D055503:Protein Multimerization; D011522:Protons; D013237:Stereoisomerism; D014981:Xenopus
chemical_list: D001426:Bacterial Proteins; D002109:Caffeic Acids; D002934:Cinnamates; D058446:Ligand-Gated Ion Channels; D011522:Protons; C029010:cinnamic acid