An Ion-Permeable State of the Glycine Receptor Captured by Molecular Dynamics

Glycine receptors (GlyR) mediate fast inhibitory neurotransmission by switching between discrete states in response to ligand-binding events. Recent high-resolution structures from cryoelectron microscopy (cryo-EM) and X-ray crystallography have provided atomistic models for the open and closed states. Notably, the cryo-EM structure in complex with glycine illuminated a previously unreported wide-open state, whose physiological significance is debated. Here, we present the structure of an ion-conducting state of GlyR alpha 1 captured by molecular dynamics and validate its physiological relevance with computational electrophysiology and polyatomic anion permeation simulations. Our analysis suggests that none of the experimental structures is a true representation of the physiologically active state, although previously characterized open channels in GLIC at pH 4, or GluCl/GlyR with ivermectin bound, provide reasonable models. These results open the door to an original functional annotation and support the conclusion that pore closing by desensitization versus deactivation involves the reorientation of the pore-lining helices in opposite directions.