ArticlePloS one2014
Molecular recognition of the neurotransmitter acetylcholine by an acetylcholine binding protein reveals determinants of binding to nicotinic acetylcholine receptors.
Article in PloS one, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 24 papers.
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Who cites it
24 citing papers in PubMed, 45 citations in OpenAlex.
- Understanding varenicline function via key receptor and ligand interactions.Cell reports. Physical science · 2025Article
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- A Pharmacophore for Drugs Targeting the α4α4 Binding Site of the (α4)Journal of neurochemistry · 2025Article
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- Origin of acetylcholine antagonism in ELIC, a bacterial pentameric ligand-gated ion channel.Communications biology · 2022Article
- Loss of Choline Agonism in the Inner Ear Hair Cell Nicotinic Acetylcholine Receptor Linked to the α10 Subunit.Frontiers in molecular neuroscience · 2021Article
- Structural insights into the putative bacterial acetylcholinesterase ChoE and its substrate inhibition mechanism.The Journal of biological chemistry · 2020Article
- In Silico Modeling of the α7 Nicotinic Acetylcholine Receptor: New Pharmacological Challenges Associated with Multiple Modes of Signaling.Mini reviews in medicinal chemistry · 2020Review
- A Functional Comparison of Homopentameric Nicotinic Acetylcholine Receptors (ACR-16) Receptors FromFrontiers in molecular neuroscience · 2020Article
- Structure-Function of Neuronal Nicotinic Acetylcholine Receptor Inhibitors Derived From Natural Toxins.Frontiers in neuroscience · 2020Review
- A single molecular distance predicts agonist binding energy in nicotinic receptors.The Journal of general physiology · 2019Article
- Understanding structure-function relationships of the human neuronal acetylcholine receptor: insights from the first crystal structures of neuronal subunits.British journal of pharmacology · 2018Review
- Makaluvamine G from the Marine Sponge Zyzzia fuliginosa Inhibits Muscle nAChR by Binding at the Orthosteric and Allosteric Sites.Marine drugs · 2018Article
- Methylpiperidinium Iodides as Novel Antagonists for α7 Nicotinic Acetylcholine Receptors.Frontiers in pharmacology · 2018Article
- Interacting amino acid replacements allow poison frogs to evolve epibatidine resistance.Science (New York, N.Y.) · 2017Article
- Differential Contribution of Subunit Interfaces to α9α10 Nicotinic Acetylcholine Receptor Function.Molecular pharmacology · 2017Article
- Molecular recognition at cholinergic synapses: acetylcholine versus choline.The Journal of physiology · 2017Article
- Structural correlates of affinity in fetal versus adult endplate nicotinic receptors.Nature communications · 2016Article
- The Ascaris suum nicotinic receptor, ACR-16, as a drug target: Four novel negative allosteric modulators from virtual screening.International journal for parasitology. Drugs and drug resistance · 2016Article
- Cation-π interactions: computational analyses of the aromatic box motif and the fluorination strategy for experimental evaluation.Physical chemistry chemical physics : PCCP · 2015Article
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Authors and funding
5 authors at 3 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Despite extensive studies on nicotinic acetylcholine receptors (nAChRs) and homologues, details of acetylcholine binding are not completely resolved. Here, we report the crystal structure of acetylcholine bound to the receptor homologue acetylcholine binding protein from Lymnaea stagnalis. This is the first structure of acetylcholine in a binding pocket containing all five aromatic residues conserved in all mammalian nAChRs. The ligand-protein interactions are characterized by contacts to the aromatic box formed primarily by residues on the principal side of the intersubunit binding interface (residues Tyr89, Trp143 and Tyr185). Besides these interactions on the principal side, we observe a cation-π interaction between acetylcholine and Trp53 on the complementary side and a water-mediated hydrogen bond from acetylcholine to backbone atoms of Leu102 and Met114, both of importance for anchoring acetylcholine to the complementary side. To further study the role of Trp53, we mutated the corresponding tryptophan in the two different acetylcholine-binding interfaces of the widespread α4β2 nAChR, i.e. the interfaces α4(+)β2(-) and α4(+)α4(-). Mutation to alanine (W82A on the β2 subunit or W88A on the α4 subunit) significantly altered the response to acetylcholine measured by oocyte voltage-clamp electrophysiology in both interfaces. This shows that the conserved tryptophan residue is important for the effects of ACh at α4β2 nAChRs, as also indicated by the crystal structure. The results add important details to the understanding of how this neurotransmitter exerts its action and improves the foundation for rational drug design targeting these receptors.
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