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Principles of activation and permeation in an anion-selective Cys-loop receptor.

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.

Pubmed ID: 21572436


  • Hibbs RE
  • Gouaux E



Publication Data

June 2, 2011

Associated Grants

  • Agency: NINDS NIH HHS, Id: F32 NS061404-01
  • Agency: NINDS NIH HHS, Id: F32 NS061404-02
  • Agency: NINDS NIH HHS, Id: F32 NS061404-03
  • Agency: NINDS NIH HHS, Id: F32NS061404
  • Agency: NINDS NIH HHS, Id: P30 NS061800
  • Agency: Howard Hughes Medical Institute, Id:

Mesh Terms

  • Animals
  • Anions
  • Binding Sites
  • Caenorhabditis elegans
  • Chloride Channels
  • Cysteine Loop Ligand-Gated Ion Channel Receptors
  • Ions
  • Models, Molecular
  • Neurotransmitter Agents
  • Protein Structure, Tertiary