title: Principles of activation and permeation in an anion-selective Cys-loop receptor.
abstract: Fast inhibitory neurotransmission is essential for nervous system function and is mediated by binding of inhibitory neurotransmitters to receptors of the Cys-loop family embedded in the membranes of neurons. Neurotransmitter binding triggers a conformational change in the receptor, opening an intrinsic chloride channel and thereby dampening neuronal excitability. Here we present the first three-dimensional structure, to our knowledge, of an inhibitory anion-selective Cys-loop receptor, the homopentameric Caenorhabditis elegans glutamate-gated chloride channel α (GluCl), at 3.3 Å resolution. The X-ray structure of the GluCl-Fab complex was determined with the allosteric agonist ivermectin and in additional structures with the endogenous neurotransmitter L-glutamate and the open-channel blocker picrotoxin. Ivermectin, used to treat river blindness, binds in the transmembrane domain of the receptor and stabilizes an open-pore conformation. Glutamate binds in the classical agonist site at subunit interfaces, and picrotoxin directly occludes the pore near its cytosolic base. GluCl provides a framework for understanding mechanisms of fast inhibitory neurotransmission and allosteric modulation of Cys-loop receptors.
authors.affiliation: Vollum Institute, Oregon Health and Science University, 3181 SW Sam Jackson Park Road, Portland, Oregon 97239, USA.
authors.forename: Ryan E
authors.initials: RE
authors.lastname: Hibbs
authors.forename: Eric
authors.initials: E
authors.lastname: Gouaux
mesh_terms: D000818:Animals; D000838:Anions; D001665:Binding Sites; D017173:Caenorhabditis elegans / Q000378:metabolism*; D018118:Chloride Channels / Q000737:chemistry* / Q000378:metabolism*; D058466:Cysteine Loop Ligand-Gated Ion Channel Receptors / Q000378:metabolism*; D007477:Ions / Q000378:metabolism; D008958:Models, Molecular; D018377:Neurotransmitter Agents / Q000378:metabolism; D017434:Protein Structure, Tertiary
chemical_list: D000838:Anions; D018118:Chloride Channels; D058466:Cysteine Loop Ligand-Gated Ion Channel Receptors; D007477:Ions; D018377:Neurotransmitter Agents; C109777:glutamate-gated chloride channels