ArticleBiophysical journal2003
Asymmetric structural motions of the homomeric alpha7 nicotinic receptor ligand binding domain revealed by molecular dynamics simulation.
Article in Biophysical journal, 2003. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 36 papers.
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Who cites it
36 citing papers in PubMed, 73 citations in OpenAlex.
- Stable desensitization of αEuropean journal of pharmacology · 2021Article
- Therapeutic Targeting ofPharmacological reviews · 2021Review
- A Computational Analysis of the Factors Governing the Dynamics of α7 nAChR and Its Homologs.Biophysical journal · 2020Article
- Nicotinic receptor pharmacology in silico: Insights and challenges.Neuropharmacology · 2020Review
- In Silico Modeling of the α7 Nicotinic Acetylcholine Receptor: New Pharmacological Challenges Associated with Multiple Modes of Signaling.Mini reviews in medicinal chemistry · 2020Review
- Allosteric Agonism ofMolecular pharmacology · 2019Article
- Macroscopic and Microscopic Activation ofMolecular pharmacology · 2019Article
- Multiple regions in the extracellular domain of the glycine receptor determine receptor activity.The Journal of biological chemistry · 2018Article
- Article
- End-plate acetylcholine receptor: structure, mechanism, pharmacology, and disease.Physiological reviews · 2012Review
- Structural link between γ-aminobutyric acid type A (GABAA) receptor agonist binding site and inner β-sheet governs channel activation and allosteric drug modulation.The Journal of biological chemistry · 2012Article
- Blockade of neuronal α7-nAChR by α-conotoxin ImI explained by computational scanning and energy calculations.PLoS computational biology · 2011Article
- Decrypting the sequence of structural events during the gating transition of pentameric ligand-gated ion channels based on an interpolated elastic network model.PLoS computational biology · 2011Article
- Unresponsive correlated motion in alpha7 nAChR to halothane binding explains its functional insensitivity to volatile anesthetics.The journal of physical chemistry. B · 2010Article
- Mapping spatial relationships between residues in the ligand-binding domain of the 5-HT3 receptor using a molecular ruler.Biophysical journal · 2010Article
- Higher susceptibility to halothane modulation in open- than in closed-channel alpha4beta2 nAChR revealed by molecular dynamics simulations.The journal of physical chemistry. B · 2010Article
- Main immunogenic region structure promotes binding of conformation-dependent myasthenia gravis autoantibodies, nicotinic acetylcholine receptor conformation maturation, and agonist sensitivity.The Journal of neuroscience : the official journal of the Society for Neuroscience · 2009Article
- Structural model of rho1 GABAC receptor based on evolutionary analysis: Testing of predicted protein-protein interactions involved in receptor assembly and function.Protein science : a publication of the Protein Society · 2009Article
- Molecular-dynamics simulations of ELIC-a prokaryotic homologue of the nicotinic acetylcholine receptor.Biophysical journal · 2009Article
- Binding of long-chain alpha-neurotoxin would stabilize the resting state of nAChR: a comparative study with alpha-conotoxin.Theoretical biology & medical modelling · 2009Article
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Authors and funding
5 authors at 3 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
A homology model of the ligand binding domain of the alpha7 nicotinic receptor is constructed based on the acetylcholine-binding protein crystal structure. This structure is refined in a 10 ns molecular dynamics simulation. The modeled structure proves fairly resilient, with no significant changes at the secondary or tertiary structural levels. The hypothesis that the acetylcholine-binding protein template is in the activated or desensitized state, and the absence of a bound agonist in the simulation suggests that the structure may also be relaxing from this state to the activatable state. Candidate motions that take place involve not only the side chains of residues lining the binding sites, but also the subunit positions that determine the overall shape of the receptor. In particular, two nonadjacent subunits move outward, whereas their partners counterclockwise to them move inward, leading to a marginally wider interface between themselves and an overall asymmetric structure. This in turn affects the binding sites, producing two that are more open and characterized by distinct side-chain conformations of W54 and L118, although motions of the side chains of all residues in every binding site still contribute to a reduction in binding site size, especially the outward motion of W148, which hinders acetylcholine binding. The Cys loop at the membrane interface also displays some flexibility. Although the short simulation timescale is unlikely to sample adequately all the conformational states, the pattern of observed motions suggests how ligand binding may correlate with larger-scale subunit motions that would connect with the transmembrane region that controls the passage of ions. Furthermore, the shape of the asymmetry with binding sites of differing affinity for acetylcholine, characteristic of other nicotinic receptors, may be a natural property of the relaxed, activatable state of alpha7.
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