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Conformational transitions and allosteric modulation in a heteromeric glycine receptor.

Eric GibbsEmily KlemmDavid SeiferthArvind KumarSerban L IlcaPhilip Charles BigginSudha Chakrapani
Published in: Nature communications (2023)
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 α1β B GlyR 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 α 1 βGlyR and provide a framework for further study of this physiologically important channel.
Keyphrases
  • spinal cord
  • molecular dynamics
  • molecular dynamics simulations
  • high resolution
  • small molecule
  • single molecule
  • spinal cord injury
  • reactive oxygen species
  • dna binding
  • crystal structure