Conformational transitions and allosteric modulation in a heteromeric glycine receptor.
Gibbs E., Klemm E., Seiferth D., Kumar A., Ilca SL., Biggin PC., Chakrapani S.
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.