Identification of cinnamic acid derivatives as novel antagonists of the prokaryotic proton-gated ion channel GLIC

Marie S. Prevost, Sandrine Delarue-Cochin, Justine Marteaux, Claire Colas, Catherine Van Renterghem, Arnaud Blondel, Thérèse Malliavin, Pierre Jean Corringer, Delphine Joseph

Research output: Contribution to journalArticlepeer-review

28 Scopus citations

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.

Original languageEnglish
Pages (from-to)4619-4630
Number of pages12
JournalJournal of Medicinal Chemistry
Volume56
Issue number11
DOIs
StatePublished - 13 Jun 2013
Externally publishedYes

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