A gating mechanism of pentameric ligand-gated ion channels
Open accessAbstract
Pentameric ligand-gated ion channels (pLGICs) play a central role in intercellular communication in the nervous system and are involved in fundamental processes such as attention, learning, and memory. They are oligomeric protein assemblies that convert a chemical signal into an ion flux through the postsynaptic membrane, but the molecular mechanism of gating ions has remained elusive. Here, we present atomistic molecular dynamics simulations of the prokaryotic channels from Gloeobacter violaceus (GLIC) and Erwinia chrysanthemi (ELIC), whose crystal structures are thought to represent the active and the resting states of pLGICs, respectively, and of the eukaryotic glutamate-gated chloride channel from Caenorhabditis elegans (GluCl), whose open-channel structure was determined complexed with the positive allosteric modulator ivermectin. Structural observables extracted from the trajectories of GLIC and ELIC are used as progress variables to analyze the time evolution of GluCl, which was simulated in the absence of ivermectin starting from the structure with bound ivermectin. The trajectory of GluCl with ivermectin removed shows a sequence of structural events that couple agonist unbinding from the extracellular domain to ion-pore closing in the transmembrane domain. Based on these results, we propose a structural mechanism for the allosteric communication leading to deactivation/activation of the GluCl channel. This model of gating emphasizes the coupling between the quaternary twisting and the opening/closing of the ion pore and is likely to apply to other members of the pLGIC family.
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MD relaxation of the open form of GluCl upon removal of ivermectin promotes partial closure of the ion pore through a complex quaternary mechanism involving global receptor twisting and radial expansion of the extracellular domain.
“Similarly, MD relaxation of the open form of the eukaryotic glutamate-gated ion channel (GluCl) upon removal of the positive allosteric modulator ivermectin, was shown to promote partial closure of the ion pore through a complex quaternary mechanism involving global receptor twisting and a radial expansion (blooming) of the extracellular domain (Calimet et al., 2013).”
From Allostery in Its Many Disguises: From Theory to Applications (2019) · cites this paper as Calimet et al., 2013
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Allostery in Its Many Disguises: From Theory to Applications
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Self-citation
- Authors
- Calimet, N., Simoes, M., Changeux, J.-P., Karplus, M., Taly, A., & Cecchini, M.
- Affiliations
- Centre National de la Recherche Scientifique (FR)
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2013-09-16
- Volume
- 110
- Issue
- 42
- Pages
- E3987-96
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC3801054
- OpenAlex
- W1950332654
- Cited by
- 150
- References
- 62
- Citations by year
- 2026: 6 · 2025: 5 · 2024: 8 · 2023: 9 · 2022: 5 · 2021: 14 · 2020: 4 · 2019: 17 · 2018: 11 · 2017: 15 · 2016: 19 · 2015: 16 · 2014: 18 · 2013: 3
- FWCI
- 1.76
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- HAL (submittedVersion)
- Funders
- Agence Nationale de la Recherche (ANR-10-LABX-0026)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Nicotinic Acetylcholine Receptors Study
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ion channel regulation and function
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Keywords
- pentameric ligand-gated ion channels, channel gating, allosteric communication, glutamate-gated chloride channels, ivermectin
- MeSH terms
- Animals, Humans, Nerve Tissue Proteins, Structure-Activity Relationship, Ion Channel Gating, Protein Structure, Secondary, Protein Structure, Tertiary, Neurotransmitter Agents, Ligand-Gated Ion Channels
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