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

Nature. 2011 Jun 2;474(7349):54-60. doi: 10.1038/nature10139. Epub 2011 May 15.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

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


  • Anions
  • Chloride Channels
  • Cysteine Loop Ligand-Gated Ion Channel Receptors
  • Ions
  • Neurotransmitter Agents
  • glutamate-gated chloride channels

Associated data

  • PDB/3RHW
  • PDB/3RI5
  • PDB/3RIA
  • PDB/3RIF