9PKX

Alpha1/Beta Heteromeric Glycine receptor in the presence of 0.200 mM strychnine and 500 nM ivermectin

Summary for 9PKX

• Entry DOI: 10.2210/pdb9pkx/pdb
• EMDB information: 71706
• Descriptor: Glycine receptor, alpha 1, Glycine receptor beta subunit 2, STRYCHNINE, ... (4 entities in total)
• Functional Keywords: ion channel, pentameric, glycine, receptor, transport protein
• Biological source: Danio rerio (zebrafish); More
• Total number of polymer chains: 5
• Total formula weight: 278748.77

Authors

Gibbs, E.,Chakrapani, S. (deposition date: 2025-07-14, release date: 2026-01-07, Last modification date: 2026-07-22)

Primary citation

Gibbs, E.,Feddersen, B.,Kindig, K.J.,Seiferth, D.,Biggin, P.C.,Chakrapani, S.
Structural basis for domain coupling in heteromeric glycine receptors revealed by an atypical allosteric agonist.
Sci Adv, 12:eaeb2036-eaeb2036, 2026

PubMed Abstract: 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.

PubMed: 41686897
DOI: 10.1126/sciadv.aeb2036

Experimental method

ELECTRON MICROSCOPY (2.86 Å)