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Mechanisms of activation and desensitization of full-length glycine receptor in lipid nanodiscs.

Kumar A, Basak S, Rao S, Gicheru Y, Mayer ML, Sansom MSP, Chakrapani S
Nat Commun 11 3752 (2020)
Related entries: 6ubt, 6ud3, 6vm0, 6vm2, 6vm3

Cited: 45 times
EuropePMC logo PMID: 32719334

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.

Reviews - 6ubs mentioned but not cited (1)

  1. Structure and Mechanism of Glycine Receptor Elucidated by Cryo-Electron Microscopy. Zhu H. Front Pharmacol 13 925116 (2022)

Articles - 6ubs mentioned but not cited (4)

  1. Insect RDL Receptor Models for Virtual Screening: Impact of the Template Conformational State in Pentameric Ligand-Gated Ion Channels. Felsztyna I, Villarreal MA, García DA, Miguel V. ACS Omega 7 1988-2001 (2022)
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Reviews citing this publication (8)

  1. Direct Structural Insights into GABAA Receptor Pharmacology. Kim JJ, Hibbs RE. Trends Biochem Sci 46 502-517 (2021)
  2. Lipid Membrane Mimetics in Functional and Structural Studies of Integral Membrane Proteins. Majeed S, Ahmad AB, Sehar U, Georgieva ER. Membranes (Basel) 11 685 (2021)
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  8. Recent Insight into Lipid Binding and Lipid Modulation of Pentameric Ligand-Gated Ion Channels. Ananchenko A, Hussein TOK, Mody D, Thompson MJ, Baenziger JE. Biomolecules 12 814 (2022)

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