Identification of Cinnamic Acid Derivatives As Novel Antagonists of the Prokaryotic Proton-Gated Ion Channel GLIC

Journal of Medicinal Chemistry (Impact Factor: 5.48). 05/2013; 56(11). DOI: 10.1021/jm400374q
Source: PubMed

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.

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    ABSTRACT: Pentameric ligand-gated ion channels (pLGICs) mediate fast chemical transmission of nerve signals in the central and peripheral nervous system. On the functional side, these molecules respond to the binding of a neurotransmitter (glycine, GABA, acetylcholine or 5HT3) in the extracellular domain (ECD) by opening their ionotropic pore in the transmembrane domain (TMD). The response to the neurotransmitter binding can be modulated by several chemical compounds acting at topographically distinct sites, as documented by a large body of literature. Notably, these receptors are the target of several classes of world-wide prescribed drugs, including general anaesthetics, smoking cessation aids, anxiolytics, anticonvulsants, muscle relaxants, hypnotics and anti-emetics. On the structural side recent progress has been made on the crystallization of pLGICs in its different allosteric states, especially pLGICs of bacterial origin. Therefore, structure-function relationships can now be discussed at atomic level for pLGICs. Scope Of Review This review focuses on the crystallographic structure of complexes of pLGICs with a number of ligands of pharmacological interest. First, we review structural data on two key functional aspects of these receptors: the agonist-induced activation and ion transport itself. The molecular understanding of both these functional aspects is important, as they are those that most pharmacological compounds target. Next, we describe modulation sites that have recently been documented by X-ray crystallography. Finally, we propose a simple geometric classification of all these pharmacological sites in pLGICs, based on icosahedrons. Major Conclusions This review illustrates the wealth of structural insight gained by comparing all available structures of members of the pLGIC family to rationalize the pharmacology of structurally-diverse drugs acting at topographically distinct sites. It will be highlighted how sites that had been described earlier using biochemical techniques can be rationalized using structural data. Surprisingly, the use of icosahedral symmetry allows to link together several modulation sites, in a way that was totally unanticipated. General Significance Overall, understanding the interplay between the different modulation sites at the structural level should help the design of future drugs targeting pLGICs. This article is part of a Special Issue entitled Structural biochemistry and biophysics of membrane proteins.
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    ABSTRACT: Pentameric ligand-gated ion channels (pLGICs) play a central role in intercellular communications in the nervous system by converting the binding of a chemical messenger—a neurotransmitter—into an ion flux through the postsynaptic membrane. They are oligomeric assemblies that provide prototypical examples of allosterically regulated integral membrane proteins. Here, we present an overview of the most recent advances on the signal transduction mechanism based on the X-ray structures of both prokaryotic and invertebrate eukaryotic pLGICs and atomistic Molecular Dynamics simulations. The present results suggest that ion gating involves a large structural reorganization of the molecule mediated by two distinct quaternary transitions, a global twisting and the blooming of the extracellular domain, which can be modulated by ligand binding at the topographically distinct orthosteric and allosteric sites. The emerging model of gating is consistent with a wealth of functional studies and will boost the development of novel pharmacological strategies.
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