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bioRxiv · 10.1101/788695

Mechanisms of activation and desensitization of full-length glycine receptor in membranes

kumar, A.·Basak, S.·Rao, S.·Gicheru, Y.·Mayer, M. L.·Sansom, M.·Chakrapani, S.
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Abstract

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.

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kumar, A., Basak, S., Rao, S., Gicheru, Y., Mayer, M. L., Sansom, M., Chakrapani, S.. 2019-09-30. Mechanisms of activation and desensitization of full-length glycine receptor in membranes. https://doi.org/10.1101/788695

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