PUBLICATION
Glycine receptor mechanism elucidated by electron cryo-microscopy
- Authors
- Du, J., Lü, W., Wu, S., Cheng, Y., Gouaux, E.
- ID
- ZDB-PUB-150908-3
- Date
- 2015
- Source
- Nature 526(7572): 224-9 (Journal)
- Registered Authors
- Keywords
- Electron microscopy, Ion channels, Membrane proteins
- MeSH Terms
-
- Allosteric Regulation
- Animals
- Binding Sites
- Cryoelectron Microscopy*
- Glycine/metabolism
- Glycine/pharmacology
- Ion Channel Gating/drug effects
- Ivermectin/metabolism
- Ivermectin/pharmacology
- Models, Molecular
- Neurotransmitter Agents/metabolism
- Neurotransmitter Agents/pharmacology
- Protein Conformation/drug effects
- Protein Subunits/chemistry
- Protein Subunits/drug effects
- Protein Subunits/metabolism
- Receptors, Glycine/agonists
- Receptors, Glycine/antagonists & inhibitors
- Receptors, Glycine/metabolism*
- Receptors, Glycine/ultrastructure*
- Rotation
- Signal Transduction
- Strychnine/metabolism
- Strychnine/pharmacology
- Zebrafish*
- PubMed
- 26344198 Full text @ Nature
Citation
Du, J., Lü, W., Wu, S., Cheng, Y., Gouaux, E. (2015) Glycine receptor mechanism elucidated by electron cryo-microscopy. Nature. 526(7572):224-9.
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.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping