ArticleThe Journal of general physiology2017
A mechanism for acetylcholine receptor gating based on structure, coupling, phi, and flip.
Article in The Journal of general physiology, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 27 papers.
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Who cites it
27 citing papers in PubMed, 60 citations in OpenAlex.
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- Dynamics of receptor activation by agonists.Biophysical journal · 2024Review
- A release of local subunit conformational heterogeneity underlies gating in a muscle nicotinic acetylcholine receptor.Nature communications · 2024Article
- Mechanism of hydrophobic gating in the acetylcholine receptor channel pore.The Journal of general physiology · 2024Article
- Mechanistic basis of ligand efficacy in the calcium-activated chloride channel TMEM16A.The EMBO journal · 2023Article
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- Illumination of a progressive allosteric mechanism mediating the glycine receptor activation.Nature communications · 2023Article
- Recent Insight into Lipid Binding and Lipid Modulation of Pentameric Ligand-Gated Ion Channels.Biomolecules · 2022Review
- Towards the Idea of Molecular Brains.International journal of molecular sciences · 2021Review
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- Agonist efficiency from concentration-response curves: Structural implications and applications.Biophysical journal · 2021Article
- A critical residue in the αeLife · 2021Article
- Loss of Choline Agonism in the Inner Ear Hair Cell Nicotinic Acetylcholine Receptor Linked to the α10 Subunit.Frontiers in molecular neuroscience · 2021Article
- Pathways for nicotinic receptor desensitization.The Journal of general physiology · 2020Article
- Structure of the Native Muscle-type Nicotinic Receptor and Inhibition by Snake Venom Toxins.Neuron · 2020Article
- Molecular dynamics simulations of dihydro-β-erythroidine bound to the human α4β2 nicotinic acetylcholine receptor.British journal of pharmacology · 2019Article
- Efficiency measures the conversion of agonist binding energy into receptor conformational change.The Journal of general physiology · 2019Article
- A single molecular distance predicts agonist binding energy in nicotinic receptors.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
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Authors and funding
4 authors at 1 institution in 1 country.
Funding
Abstract
Nicotinic acetylcholine receptors are allosteric proteins that generate membrane currents by isomerizing ("gating") between resting and active conformations under the influence of neurotransmitters. Here, to explore the mechanisms that link the transmitter-binding sites (TBSs) with the distant gate, we use mutant cycle analyses to measure coupling between residue pairs, phi value analyses to sequence domain rearrangements, and current simulations to reproduce a microsecond shut component ("flip") apparent in single-channel recordings. Significant interactions between amino acids separated by >15 Å are rare; an exception is between the αM2-M3 linkers and the TBSs that are ∼30 Å apart. Linker residues also make significant, local interactions within and between subunits. Phi value analyses indicate that without agonists, the linker is the first region in the protein to reach the gating transition state. Together, the phi pattern and flip component suggest that a complete, resting↔active allosteric transition involves passage through four brief intermediate states, with brief shut events arising from sojourns in all or a subset. We derive energy landscapes for gating with and without agonists, and propose a structure-based model in which resting→active starts with spontaneous rearrangements of the M2-M3 linkers and TBSs. These conformational changes stabilize a twisted extracellular domain to promote transmembrane helix tilting, gate dilation, and the formation of a "bubble" that collapses to initiate ion conduction. The energy landscapes suggest that twisting is the most energetically unfavorable step in the resting→active conformational change and that the rate-limiting step in the reverse process is bubble formation.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.