X-ray structures of GluCl in apo states reveal a gating mechanism of Cys-loop receptors

Thorsten Althoff, Ryan E. Hibbs, Surajit Banerjee, Eric Gouaux

Research output: Contribution to journalArticle

144 Citations (Scopus)

Abstract

Cys-loop receptors are neurotransmitter-gated ion channels that are essential mediators of fast chemical neurotransmission and are associated with a large number of neurological diseases and disorders, as well as parasitic infections1-4. Members of this ion channel superfamily mediate excitatory or inhibitory neurotransmission depending on their ligand and ion selectivity. Structural information for Cys-loop receptors comes from several sources including electron microscopic studies of the nicotinic acetylcholine receptor5, high-resolution X-ray structures of extracellular domains6 and X-ray structures of bacterial orthologues 7-10. In 2011 our group published structures of the Caenorhabditis elegans glutamate-gated chloride channel (GluCl) in complex with the allosteric partial agonist ivermectin, which provided insights into the structure of a possibly open state of a eukaryotic Cys-loop receptor, the basis for anion selectivity and channel block, and the mechanism by which ivermectin and related molecules stabilize the open state and potentiate neurotransmitter binding 11. However, there remain unanswered questions about the mechanism of channel opening and closing, the location and nature of the shut ion channel gate, the transitions between the closed/resting, open/activated and closed/desensitized states, and the mechanism by which conformational changes are coupled between the extracellular, orthosteric agonist binding domain and the transmembrane, ion channel domain. Here we present two conformationally distinct structures of C. elegans GluCl in the absence of ivermectin. Structural comparisons reveal a quaternary activation mechanism arising from rigid-body movements between the extracellular and transmembrane domains and a mechanism for modulation of the receptor by phospholipids.

Original languageEnglish (US)
Pages (from-to)333-337
Number of pages5
JournalNature
Volume512
Issue number7514
DOIs
StatePublished - Aug 21 2014

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Cysteine Loop Ligand-Gated Ion Channel Receptors
Ion Channels
Ivermectin
X-Rays
Caenorhabditis elegans
Synaptic Transmission
Neurotransmitter Agents
Bacterial Structures
Nervous System Diseases
Acetylcholine
Anions
Phospholipids
Electrons
Ions
Ligands
glutamate-gated chloride channels

ASJC Scopus subject areas

  • General

Cite this

X-ray structures of GluCl in apo states reveal a gating mechanism of Cys-loop receptors. / Althoff, Thorsten; Hibbs, Ryan E.; Banerjee, Surajit; Gouaux, Eric.

In: Nature, Vol. 512, No. 7514, 21.08.2014, p. 333-337.

Research output: Contribution to journalArticle

Althoff, Thorsten ; Hibbs, Ryan E. ; Banerjee, Surajit ; Gouaux, Eric. / X-ray structures of GluCl in apo states reveal a gating mechanism of Cys-loop receptors. In: Nature. 2014 ; Vol. 512, No. 7514. pp. 333-337.
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