Structural basis for domain coupling in heteromeric glycine receptors revealed by an atypical allosteric agonist

Journal article

Glycine receptors (GlyRs), pentameric ligand-gated ion channels (pLGICs), mediate sensory and motor functions. GlyR functional states are well characterized; however, structural details of transitions between states remain undefined. Here, we determined cryo-electron microscopy structures of GlyRα1β (with gephyrin E-domain) at varying concentrations of ivermectin, a transmembrane domain (TMD) allosteric agonist, and at saturating concentrations of strychnine, a competitive antagonist at the extracellular domain (ECD). Electrophysiology shows that ivermectin activates GlyR even with strychnine present. Structures with both ligands reveal intermediate states featuring a desensitized TMD and an ECD between closed and desensitized conformations, providing insights into domain cooperativity and ligand efficacy. Molecular dynamics simulations show how ivermectin affects strychnine dynamics. These data support a model where ivermectin activates GlyRs through a concerted and near-symmetric TMD mechanism, whereas allosteric ECD motions are graded and spatially heterogeneous. These findings reveal unanticipated features of GlyR gating and establish principles of allosteric modulation applicable to pLGICs.

Authors: Gibbs, E; Feddersen, B; Kindig, KJ; Seiferth, D; Biggin, PC

• Publication status: Published
• Peer review status: Peer reviewed
• Publisher: American Association for the Advancement of Science
• Journal: Science Advances
• Volume: 12
• Issue: 7
• Pages: eaeb2036
• Article number: eaeb2036
• Publication date: 2026-02-13
• DOI: 10.1126/sciadv.aeb2036
• EISSN: 2375-2548
• ISSN: 2375-2548
• Pmid: 41686897
• Language: English
• Keywords: Molecular Dynamics Simulation; Humans; Protein Multimerization; Ivermectin; Animals; Receptors, Glycine; Strychnine; Cryoelectron Microscopy; Protein Domains; Allosteric Regulation; Ligands