Mechanisms of activation and desensitization of full-length glycine receptor in lipid nanodiscs
Year: 2020
Type: article
Abstract: Glycinergic synapses play a central role in motor control and pain processing in the central nervous system. Glycine receptors (GlyRs) are key players in mediating fast inhibitory neurotransmission at these synapses. While previous high-resolution structures have provided insights into the molecular architecture of GlyR, several mechanistic questions pertaining to channel function are still unanswered. Here, we present Cryo-EM structures of the full-length GlyR protein complex reconstituted into lipid nanodiscs that are captured in the unliganded (closed), glycine-bound (open and desensitized), and allosteric modulator-bound conformations. A comparison of these states reveals global conformational changes underlying GlyR channel gating and modulation. The functional state assignments were validated by molecular dynamics simulations, and the observed permeation events are in agreement with the anion selectivity and conductance of GlyR. These studies provide the structural basis for gating, ion selectivity, and single-channel conductance properties of GlyR in a lipid environment.
Source: Nature Communications
Language: English
Subfield: Cellular and Molecular Neuroscience
Field: Neuroscience
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $5,380
Funders: U.S. Department of Health and Human Services, American Heart Association, Case Western Reserve University, Frederick National Laboratory for Cancer Research, National Institutes of Health, Engineering and Physical Sciences Research Council, National Cancer Institute, National Institute of General Medical Sciences, SLAC National Accelerator Laboratory
Awards: G1672821126, G2087520253, Effects of cholesterol and polyunsaturated fatty acids on ligand-gated ion channel structure and function, G2571061048, G2900223236, The UK High-End Computing Consortium for Biomolecular Simulation, Mechanisms underlying gating and modulation of Glycine receptor using CryoEM, Molecular Mechanisms of Desensitization and Drug Modulation in Ligand-Gated Ion C, G5001634773, G55144381, Structure and Function of Pentameric Ligand-Gated Ion Channels, G6317498416, G6905502837, 3 D Electron Microscopy of Macromolecules, G9000029263, G9000069187, G9000097965
OpenAlex ID: W3045228316