title: A gating mechanism of pentameric ligand-gated ion channels.
abstract: Pentameric ligand-gated ion channels (pLGICs) play a central role in intercellular communication in the nervous system and are involved in fundamental processes such as attention, learning, and memory. They are oligomeric protein assemblies that convert a chemical signal into an ion flux through the postsynaptic membrane, but the molecular mechanism of gating ions has remained elusive. Here, we present atomistic molecular dynamics simulations of the prokaryotic channels from Gloeobacter violaceus (GLIC) and Erwinia chrysanthemi (ELIC), whose crystal structures are thought to represent the active and the resting states of pLGICs, respectively, and of the eukaryotic glutamate-gated chloride channel from Caenorhabditis elegans (GluCl), whose open-channel structure was determined complexed with the positive allosteric modulator ivermectin. Structural observables extracted from the trajectories of GLIC and ELIC are used as progress variables to analyze the time evolution of GluCl, which was simulated in the absence of ivermectin starting from the structure with bound ivermectin. The trajectory of GluCl with ivermectin removed shows a sequence of structural events that couple agonist unbinding from the extracellular domain to ion-pore closing in the transmembrane domain. Based on these results, we propose a structural mechanism for the allosteric communication leading to deactivation/activation of the GluCl channel. This model of gating emphasizes the coupling between the quaternary twisting and the opening/closing of the ion pore and is likely to apply to other members of the pLGIC family.
authors.affiliation: Institut de Science et d'Ingénierie Supramoléculaires, Unité Mixte de Recherche 7006, Centre National de la Recherche Scientifique, Université de Strasbourg, F-67083 Strasbourg Cedex, France.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Calimet
authors.forename: Manuel
authors.initials: M
authors.lastname: Simoes
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Changeux
authors.forename: Martin
authors.initials: M
authors.lastname: Karplus
authors.forename: Antoine
authors.initials: A
authors.lastname: Taly
authors.forename: Marco
authors.initials: M
authors.lastname: Cecchini
mesh_terms: D000818:Animals; D006801:Humans; D015640:Ion Channel Gating / Q000502:physiology*; D058446:Ligand-Gated Ion Channels / Q000737:chemistry / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000737:chemistry / Q000378:metabolism; D018377:Neurotransmitter Agents / Q000737:chemistry / Q000378:metabolism; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D013329:Structure-Activity Relationship
chemical_list: D058446:Ligand-Gated Ion Channels; D009419:Nerve Tissue Proteins; D018377:Neurotransmitter Agents
keywords: chemo-electrical transduction; ion channel gating; neurotransmitter receptors
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