Structural Investigation into Gating and Modulation of Alpha1 Glycine Receptor in Lipid Nanodiscs

Abstract

Glycine receptors (GlyR) mediate fast chemical transmission of synaptic signals in the central and peripheral nervous system. GlyR are anionic members of pentameric ligand gated ion channels and are central players in motor coordination and pain perception. Potentiation of GlyR activity results in dampening pain signals in the spinal cord making these receptors an attractive target for pain therapy. Here, we present Cryo-EM structures of the full-length alpha1 GlyR reconstituted into lipid nanodiscs that are captured in multiple functional states that include, the unliganded state (closed) and glycine-bound conformations (open and desensitized). in addition, we present conformations of GlyR in various ligand-bound forms that provide insights into the mechanisms underlying allosteric modulation. The functional state assignments were validated by molecular dynamics simulations. A comparison of these states reveals global conformational changes underlying GlyR channel gating and modulation.