title: Allosteric regulation of pentameric ligand-gated ion channels: an emerging mechanistic perspective.
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.
authors.forename: Antoine
authors.initials: A
authors.lastname: Taly
authors.forename: Jérôme
authors.initials: J
authors.lastname: Hénin
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Changeux
authors.forename: Marco
authors.initials: M
authors.lastname: Cecchini
mesh_terms: D000494:Allosteric Regulation; D000818:Animals; D006801:Humans; D015640:Ion Channel Gating; D058446:Ligand-Gated Ion Channels / Q000737:chemistry* / Q000378:metabolism*; D008958:Models, Molecular; D055503:Protein Multimerization; D054852:Small Molecule Libraries / Q000378:metabolism
chemical_list: D058446:Ligand-Gated Ion Channels; D054852:Small Molecule Libraries