A Refined Open State of the Glycine Receptor Obtained via Molecular Dynamics Simulations

Summary

Pentameric ligand-gated ion channels are key players in mediating fast neurotransmission. Glycine receptors are chloride-selective members of this receptor family that mediate inhibitory synaptic transmission and are implicated in neurological disorders including autism and hyperekplexia. They have been structurally characterized by both X-ray crystallography and cryoelectron microscopy (cryo-EM) studies, with the latter giving rise to what was proposed as a possible open state. However, recent work has questioned the physiological relevance of this open state structure, since it rapidly collapses in molecular dynamics simulations. Here, we show that the collapse can be avoided by a careful equilibration protocol that reconciles the more problematic regions of the original density map and gives a stable open state that shows frequent selective chloride permeation. The protocol developed in this work provides a means to refine open-like structures of the whole pentameric ligand-gated ion channel superfamily and reconciles the previous issues with the cryo-EM structure.

Graphical Abstract

Highlights

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  MD is used to refine problematic regions of the open state of the glycine receptor

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  We functionally annotate it as open and selective for chloride ions

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  The open state is stabilized by the 9′ residues entering conserved hydrophobic pockets

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  The protocol can be more broadly applied to all members of the Cys-loop family

Abstract

Dmgen and Biggin use a molecular dynamics protocol to refine problematic regions of the open state cryo-EM structure of the glycine receptor. They demonstrate that a stable open state is achieved when the leucine gate residues at the 9′ position move into well-conserved hydrophobic pockets at the interface between subunits.