PUBLICATION
Mechanisms of activation and desensitization of full-length glycine receptor in lipid nanodiscs
- Authors
- Kumar, A., Basak, S., Rao, S., Gicheru, Y., Mayer, M.L., Sansom, M.S.P., Chakrapani, S.
- ID
- ZDB-PUB-200909-1
- Date
- 2020
- Source
- Nature communications 11: 3752 (Journal)
- Registered Authors
- Keywords
- none
- MeSH Terms
-
- Xenopus
- Allosteric Regulation
- Animals
- Zebrafish Proteins/metabolism*
- Zebrafish Proteins/ultrastructure
- Glycine/metabolism
- Nanoparticles/chemistry*
- Receptors, Glycine/metabolism*
- Receptors, Glycine/ultrastructure
- Lipids/chemistry*
- Molecular Dynamics Simulation
- Binding Sites
- Protein Conformation
- Ion Channel Gating*
- Neurotransmitter Agents/metabolism
- PubMed
- 32719334 Full text @ Nat. Commun.
Citation
Kumar, A., Basak, S., Rao, S., Gicheru, Y., Mayer, M.L., Sansom, M.S.P., Chakrapani, S. (2020) Mechanisms of activation and desensitization of full-length glycine receptor in lipid nanodiscs. Nature communications. 11:3752.
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.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping