ArticlePLoS computational biology2017
Un-gating and allosteric modulation of a pentameric ligand-gated ion channel captured by molecular dynamics.
Article in PLoS computational biology, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 19 papers.
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Who cites it
19 citing papers in PubMed.
- Hidden complexity of α7 nicotinic acetylcholine receptor desensitization revealed by MD simulations and Markov state modeling.Proceedings of the National Academy of Sciences of the United States of America · 2025Article
- Mechanism of hydrophobic gating in the acetylcholine receptor channel pore.The Journal of general physiology · 2024Article
- Allosteric modulation of α1β3γ2 GABABiophysical journal · 2023Article
- Illumination of a progressive allosteric mechanism mediating the glycine receptor activation.Nature communications · 2023Article
- Wordom update 2: A user-friendly program for the analysis of molecular structures and conformational ensembles.Computational and structural biotechnology journal · 2023Article
- Computational methods and theory for ion channel research.Advances in physics: X · 2022Article
- Exploring the Conformational Impact of Glycine Receptor TM1-2 Mutations Through Coarse-Grained Analysis and Atomistic Simulations.Frontiers in molecular biosciences · 2022Article
- Molecular Simulations of Hydrophobic Gating of Pentameric Ligand Gated Ion Channels: Insights into Water and Ions.The journal of physical chemistry. B · 2021Article
- Community Network Analysis of Allosteric Proteins.Methods in molecular biology (Clifton, N.J.) · 2021Article
- Microsecond-timescale simulations suggest 5-HT-mediated preactivation of the 5-HTProceedings of the National Academy of Sciences of the United States of America · 2020Article
- Exploring Allosteric Pathways of a V-Type Enzyme with Dynamical Perturbation Networks.The journal of physical chemistry. B · 2019Article
- Allostery in Its Many Disguises: From Theory to Applications.Structure (London, England : 1993) · 2019Review
- A single molecular distance predicts agonist binding energy in nicotinic receptors.The Journal of general physiology · 2019Article
- Efficiency measures the conversion of agonist binding energy into receptor conformational change.The Journal of general physiology · 2019Article
- Electrostatics, proton sensor, and networks governing the gating transition in GLIC, a proton-gated pentameric ion channel.Proceedings of the National Academy of Sciences of the United States of America · 2018Article
- The neural γJournal of molecular modeling · 2018Article
- The nicotinic acetylcholine receptor: a typical 'allosteric machine'.Philosophical transactions of the Royal Society of London. Series B, Biological sciences · 2018Review
- An overview of recent molecular dynamics applications as medicinal chemistry tools for the undruggable site challenge.MedChemComm · 2018Review
- The dual-gate model for pentameric ligand-gated ion channels activation and desensitization.The Journal of physiology · 2018Review
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5 authors.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Pentameric ligand-gated ion channels (pLGICs) mediate intercellular communication at synapses through the opening of an ion pore in response to the binding of a neurotransmitter. Despite the increasing availability of high-resolution structures of pLGICs, a detailed understanding of the functional isomerization from closed to open (gating) and back is currently missing. Here, we provide the first atomistic description of the transition from open to closed (un-gating) in the glutamate-gated chloride channel (GluCl) from Caenorhabditis Elegans. Starting with the active-state structure solved in complex with the neurotransmitter L-glutamate and the positive allosteric modulator (PAM) ivermectin, we analyze the spontaneous relaxation of the channel upon removal of ivermectin by explicit solvent/membrane Molecular Dynamics (MD) simulations. The μs-long trajectories support the conclusion that ion-channel deactivation is mediated by two distinct quaternary transitions, i.e. a global receptor twisting followed by the radial expansion (or blooming) of the extracellular domain. At variance with previous models, we show that pore closing is exclusively regulated by the global twisting, which controls the position of the β1-β2 loop relative to the M2-M3 loop at the EC/TM domain interface. Additional simulations with L-glutamate restrained to the crystallographic binding mode and ivermectin removed indicate that the same twisting isomerization is regulated by agonist binding at the orthosteric site. These results provide a structural model for gating in pLGICs and suggest a plausible mechanism for the pharmacological action of PAMs in this neurotransmitter receptor family. The simulated un-gating converges to the X-ray structure of GluCl resting state both globally and locally, demonstrating the predictive character of state-of-art MD simulations.
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