Conformational transitions and allosteric modulation in a heteromeric glycine receptor

Journal article

AbstractGlycine 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.

Authors: Gibbs, E; Klemm, E; Seiferth, D; Kumar, A; Ilca, SL

• Publication status: Published
• Peer review status: Peer reviewed
• Publisher: Nature Research
• Journal: Nature Communications
• Volume: 14
• Issue: 1
• Pages: 1363-1363
• Article number: 1363
• Publication date: 2023-03-13
• DOI: 10.1038/s41467-023-37106-7
• EISSN: 2041-1723
• ISSN: 2041-1723
• Language: English
• Keywords: Ion channel; Allosteric modulator; Biochemistry; Homomeric; Glycine; Allosteric regulation; Strychnine; Protein subunit; Biology; Receptor; Amino acid; Biophysics; Chemistry; Glycine receptor