Glycine receptor mechanism elucidated by electron cryo-microscopy

Juan Du, Wei Lü, Shenping Wu, Yifan Cheng, Eric Gouaux

Research output: Contribution to journalArticle

187 Citations (Scopus)

Abstract

The strychnine-sensitive glycine receptor (GlyR) mediates inhibitory synaptic transmission in the spinal cord and brainstem and is linked to neurological disorders, including autism and hyperekplexia. Understanding of molecular mechanisms and pharmacology of glycine receptors has been hindered by a lack of high-resolution structures. Here we report electron cryo-microscopy structures of the zebrafish α1 GlyR with strychnine, glycine, or glycine and ivermectin (glycine/ivermectin). Strychnine arrests the receptor in an antagonist-bound closed ion channel state, glycine stabilizes the receptor in an agonist-bound open channel state, and the glycine/ivermectin complex adopts a potentially desensitized or partially open state. Relative to the glycine-bound state, strychnine expands the agonist-binding pocket via outward movement of the C loop, promotes rearrangement of the extracellular and transmembrane domain 'wrist' interface, and leads to rotation of the transmembrane domain towards the pore axis, occluding the ion conduction pathway. These structures illuminate the GlyR mechanism and define a rubric to interpret structures of Cys-loop receptors.

Original languageEnglish (US)
Pages (from-to)224-229
Number of pages6
JournalNature
Volume526
Issue number7572
DOIs
StatePublished - Oct 8 2015

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Glycine Receptors
Cryoelectron Microscopy
Strychnine
Glycine
Ivermectin
Cysteine Loop Ligand-Gated Ion Channel Receptors
Zebrafish
Autistic Disorder
Nervous System Diseases
Wrist
Ion Channels
Synaptic Transmission
Brain Stem
Spinal Cord
Pharmacology
Ions

ASJC Scopus subject areas

  • General

Cite this

Glycine receptor mechanism elucidated by electron cryo-microscopy. / Du, Juan; Lü, Wei; Wu, Shenping; Cheng, Yifan; Gouaux, Eric.

In: Nature, Vol. 526, No. 7572, 08.10.2015, p. 224-229.

Research output: Contribution to journalArticle

Du, Juan ; Lü, Wei ; Wu, Shenping ; Cheng, Yifan ; Gouaux, Eric. / Glycine receptor mechanism elucidated by electron cryo-microscopy. In: Nature. 2015 ; Vol. 526, No. 7572. pp. 224-229.
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