ArticleThe Journal of biological chemistry2014
Structural and functional studies of the modulator NS9283 reveal agonist-like mechanism of action at α4β2 nicotinic acetylcholine receptors.
Article in The Journal of biological chemistry, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 25 papers.
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Who cites it
25 citing papers in PubMed.
- Determining the molecular and physiological actions of subtype-selective nanobodies of GABAScience advances · 2026Article
- Understanding varenicline function via key receptor and ligand interactions.Cell reports. Physical science · 2025Article
- A Pharmacophore for Drugs Targeting the α4α4 Binding Site of the (α4)Journal of neurochemistry · 2025Article
- Efficient Expression inMolecules (Basel, Switzerland) · 2024Article
- SR9883 is a novel small-molecule enhancer of α4β2* nicotinic acetylcholine receptor signaling that decreases intravenous nicotine self-administration in rats.Frontiers in molecular neuroscience · 2024Article
- Xanomeline restores endogenous nicotinic acetylcholine receptor signaling in mouse prefrontal cortex.Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology · 2023Article
- Stoichiometry-Selective Antagonism of α4β2 Nicotinic Acetylcholine Receptors by Fluoroquinolone Antibiotics.ACS chemical neuroscience · 2022Article
- Concatemers to re-investigate the role of α5 in α4β2 nicotinic receptors.Cellular and molecular life sciences : CMLS · 2021Article
- Article
- Heterologous expression of concatenated nicotinic ACh receptors: Pros and cons of subunit concatenation and recommendations for construct designs.British journal of pharmacology · 2020Article
- Allosterism of Nicotinic Acetylcholine Receptors: Therapeutic Potential for Neuroinflammation Underlying Brain Trauma and Degenerative Disorders.International journal of molecular sciences · 2020Review
- Examining the Effects of (α4)3(β2)2 Nicotinic Acetylcholine Receptor-Selective Positive Allosteric Modulator on Acute Thermal Nociception in Rats.Molecules (Basel, Switzerland) · 2020Article
- Potentiation of a neuronal nicotinic receptor via pseudo-agonist site.Cellular and molecular life sciences : CMLS · 2019Article
- Galantamine is not a positive allosteric modulator of human α4β2 or α7 nicotinic acetylcholine receptors.British journal of pharmacology · 2018Article
- Orthosteric and allosteric potentiation of heteromeric neuronal nicotinic acetylcholine receptors.British journal of pharmacology · 2018Review
- Nicotinic acetylcholine receptors in neuropathic and inflammatory pain.FEBS letters · 2018Review
- Concatenated nicotinic acetylcholine receptors: A gift or a curse?The Journal of general physiology · 2018Article
- LY2087101 and dFBr share transmembrane binding sites in the (α4)3(β2)2 Nicotinic Acetylcholine Receptor.Scientific reports · 2018Article
- Enantiomeric barbiturates bind distinct inter- and intrasubunit binding sites in a nicotinic acetylcholine receptor (nAChR).The Journal of biological chemistry · 2017Article
- Unraveling amino acid residues critical for allosteric potentiation of (α4)3(β2)2-type nicotinic acetylcholine receptor responses.The Journal of biological chemistry · 2017Article
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5 authors.
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Abstract
Modulation of Cys loop receptor ion channels is a proven drug discovery strategy, but many underlying mechanisms of the mode of action are poorly understood. We report the x-ray structure of the acetylcholine-binding protein from Lymnaea stagnalis with NS9283, a stoichiometry selective positive modulator that targets the α4-α4 interface of α4β2 nicotinic acetylcholine receptors (nAChRs). Together with homology modeling, mutational data, quantum mechanical calculations, and pharmacological studies on α4β2 nAChRs, the structure reveals a modulator binding mode that overlaps the α4-α4 interface agonist (acetylcholine)-binding site. Analysis of contacts to residues known to govern agonist binding and function suggests that modulation occurs by an agonist-like mechanism. Selectivity for α4-α4 over α4-β2 interfaces is determined mainly by steric restrictions from Val-136 on the β2-subunit and favorable interactions between NS9283 and His-142 at the complementary side of α4. In the concentration ranges where modulation is observed, its selectivity prevents NS9283 from directly activating nAChRs because activation requires coordinated action from more than one interface. However, we demonstrate that in a mutant receptor with one natural and two engineered α4-α4 interfaces, NS9283 is an agonist. Modulation via extracellular binding sites is well known for benzodiazepines acting at γ-aminobutyric acid type A receptors. Like NS9283, benzodiazepines increase the apparent agonist potency with a minimal effect on efficacy. The shared modulatory profile along with a binding site located in an extracellular subunit interface suggest that modulation via an agonist-like mechanism may be a common mechanism of action that potentially could apply to Cys loop receptors beyond the α4β2 nAChRs.
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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.