ArticleThe Journal of neuroscience : the official journal of the Society for Neuroscience2004
Tyrosine residues that control binding and gating in the 5-hydroxytryptamine3 receptor revealed by unnatural amino acid mutagenesis.
Article in The Journal of neuroscience : the official journal of the Society for Neuroscience, 2004. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 41 papers.
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Who cites it
41 citing papers in PubMed.
- Mapping the molecular motions of 5-HTeLife · 2024Article
- Article
- Differential Regulation of Human Serotonin Receptor Type 3A by Chanoclavine and Ergonovine.Molecules (Basel, Switzerland) · 2021Article
- Structure, Function and Physiology of 5-Hydroxytryptamine Receptors Subtype 3.Sub-cellular biochemistry · 2021Review
- High-resolution structures of multiple 5-HTeLife · 2020Article
- Mutagenesis computer experiments in pentameric ligand-gated ion channels: the role of simulation tools with different resolution.Interface focus · 2019Review
- Molecular and pharmacological characterization of an acetylcholine-gated chloride channel (ACC-2) from the parasitic nematode Haemonchus contortus.International journal for parasitology. Drugs and drug resistance · 2018Article
- The binding orientations of structurally-related ligands can differ; A cautionary note.Neuropharmacology · 2017Article
- Varenicline Interactions at the 5-HT3 Receptor Ligand Binding Site are Revealed by 5-HTBP.ACS chemical neuroscience · 2015Article
- Atom-by-atom engineering of voltage-gated ion channels: magnified insights into function and pharmacology.The Journal of physiology · 2015Review
- Allosteric activation of the 5-HT3AB receptor by mCPBG.Neuropharmacology · 2015Article
- Incorporation of Non-Canonical Amino Acids.Advances in experimental medicine and biology · 2015Review
- Article
- Unraveling mechanisms underlying partial agonism in 5-HT3A receptors.The Journal of neuroscience : the official journal of the Society for Neuroscience · 2014Article
- Functional probes of drug-receptor interactions implicated by structural studies: Cys-loop receptors provide a fertile testing ground.Journal of medicinal chemistry · 2014Review
- Principles of agonist recognition in Cys-loop receptors.Frontiers in physiology · 2014Review
- Structure-activity relationships of quinoxaline-based 5-HT3A and 5-HT3AB receptor-selective ligands.ChemMedChem · 2013Article
- Structural basis of ligand recognition in 5-HT3 receptors.EMBO reports · 2013Article
- Design, synthesis, and structure-activity relationships of highly potent 5-HT₃ receptor ligands.Journal of medicinal chemistry · 2012Article
- Development and validation of quantitative structure-activity relationship models for compounds acting on serotoninergic receptors.TheScientificWorldJournal · 2012Article
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5 authors.
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Abstract
The mechanism by which agonist binding triggers pore opening in ligand-gated ion channels is poorly understood. Here, we used unnatural amino acid mutagenesis to introduce subtle changes to the side chains of tyrosine residues (Tyr141, Tyr143, Tyr153, and Tyr234), which dominate the 5-HT3 receptor binding site. Heterologous expression in oocytes, combined with radioligand binding data and a model of 5-HT (serotonin) computationally docked into the binding site, has allowed us to determine which of these residues are responsible for binding and/or gating. We have shown that Tyr 143 forms a hydrogen bond that is essential for receptor gating but does not affect binding, whereas a hydrogen bond formed by Tyr153 is involved in both binding and gating of the receptor. The aromatic group of Tyr234 is essential for binding and gating, whereas its hydroxyl does not affect binding but plays a steric role in receptor gating. Tyr141 is not involved in agonist binding or receptor gating but is important for antagonist interactions. These data, combined with a new model of the nonliganded 5-HT3 receptor, lead to a mechanistic explanation of the interactions that initiate the conformational change leading to channel opening. Thus, we suggest that agonist entry into the binding pocket may displace Tyr143 and Tyr153 and results in their forming new hydrogen bonds. These bonds may form part of the network of bond rearrangements that trigger the conformational change leading to channel opening. Similar rearrangements may initiate gating in all Cys-loop receptors.
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