Conformational transitions and allosteric modulation in a heteromeric glycine receptor

Eric Gibbs, Emily Klemm, David Seiferth, Arvind Kumar, Serban L. Ilca, Philip C. Biggin and Sudha Chakrapani ()
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Eric Gibbs: Case Western Reserve University
Emily Klemm: Case Western Reserve University
David Seiferth: University of Oxford
Arvind Kumar: Case Western Reserve University
Serban L. Ilca: New York Structural Biology Center
Philip C. Biggin: University of Oxford
Sudha Chakrapani: Case Western Reserve University

Nature Communications, 2023, vol. 14, issue 1, 1-15

Abstract: 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.

Date: 2023
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DOI: 10.1038/s41467-023-37106-7

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