PUBLICATION
Conformational transitions and allosteric modulation in a heteromeric glycine receptor
- Authors
- Gibbs, E., Klemm, E., Seiferth, D., Kumar, A., Ilca, S.L., Biggin, P.C., Chakrapani, S.
- ID
- ZDB-PUB-230315-33
- Date
- 2023
- Source
- Nature communications 14: 13631363 (Journal)
- Registered Authors
- Keywords
- none
- MeSH Terms
-
- Animals
- Strychnine*/pharmacology
- Ivermectin/pharmacology
- Zebrafish/metabolism
- Glycine/metabolism
- Receptors, Glycine*/metabolism
- PubMed
- 36914669 Full text @ Nat. Commun.
Citation
Gibbs, E., Klemm, E., Seiferth, D., Kumar, A., Ilca, S.L., Biggin, P.C., Chakrapani, S. (2023) Conformational transitions and allosteric modulation in a heteromeric glycine receptor. Nature communications. 14:13631363.
Abstract
Glycine Receptors (GlyRs) provide inhibitory neuronal input in the spinal cord and brainstem, which is critical for muscle coordination and sensory perception. Synaptic GlyRs are a heteromeric assembly of α and β subunits. Here we present cryo-EM structures of full-length zebrafish α1βBGlyR in the presence of an antagonist (strychnine), agonist (glycine), or agonist with a positive allosteric modulator (glycine/ivermectin). Each structure shows a distinct pore conformation with varying degrees of asymmetry. Molecular dynamic simulations found the structures were in a closed (strychnine) and desensitized states (glycine and glycine/ivermectin). Ivermectin binds at all five interfaces, but in a distinct binding pose at the β-α interface. Subunit-specific features were sufficient to solve structures without a fiduciary marker and to confirm the 4α:1β stoichiometry recently observed. We also report features of the extracellular and intracellular domains. Together, our results show distinct compositional and conformational properties of α1βGlyR and provide a framework for further study of this physiologically important channel.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping