RT Journal Article SR Electronic T1 Mechanisms of activation and desensitization of full-length glycine receptor in membranes JF bioRxiv FD Cold Spring Harbor Laboratory SP 788695 DO 10.1101/788695 A1 Arvind Kumar A1 Sandip Basak A1 Shanlin Rao A1 Yvonne Gicheru A1 Megan L. Mayer A1 Mark S.P Sansom A1 Sudha Chakrapani YR 2019 UL http://biorxiv.org/content/early/2019/09/30/788695.abstract AB Glycinergic synapses play a central role in motor control and pain processing in the central nervous system. Glycine receptors (GlyR) are key players in mediating fast inhibitory neurotransmission at these synapses. While previous high-resolution structural studies have provided insights into the molecular architecture of GlyR, several mechanistic questions pertaining to channel function are still unknown. Here, we present Cryo-EM structures of the full-length GlyR protein reconstituted into lipid nanodiscs that are captured in the unliganded (closed) and glycine-bound (open and desensitized) conformations. A comparison of the three states reveals global conformational changes underlying GlyR channel gating. The functional state assignments were validated by molecular dynamics simulations of the structures incorporated in a lipid bilayer. Observed permeation events are in agreement with the anion selectivity of the channel and the reported single-channel conductance of GlyR. These studies establish the structural basis for gating, selectivity, and single-channel conductance of GlyR in a physiological environment.