3 research outputs found
Therapeutic Effects of Anti-CD115 Monoclonal Antibody in Mouse Cancer Models through Dual Inhibition of Tumor-Associated Macrophages and Osteoclasts
Identification of Cinnamic Acid Derivatives As Novel Antagonists of the Prokaryotic Proton-Gated Ion Channel GLIC
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