ArticleThe Journal of biological chemistry2012
Intersubunit bridge formation governs agonist efficacy at nicotinic acetylcholine α4β2 receptors: unique role of halogen bonding revealed.
Article in The Journal of biological chemistry, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 19 papers.
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Who cites it
19 citing papers in PubMed, 47 citations in OpenAlex.
- Unveiling an Alternative Mechanism for Lewis Basic Selenium as a C─H Hydrogen Bond Catalyst and Its Application in the Halogenation of Arenes.Angewandte Chemie (International ed. in English) · 2025Article
- Highlights on U.S. FDA-approved halogen-containing drugs in 2024.European journal of medicinal chemistry · 2025Review
- A Pharmacophore for Drugs Targeting the α4α4 Binding Site of the (α4)Journal of neurochemistry · 2025Article
- In Silico Modeling of the α7 Nicotinic Acetylcholine Receptor: New Pharmacological Challenges Associated with Multiple Modes of Signaling.Mini reviews in medicinal chemistry · 2020Review
- Halogen-π Interactions in the Cytochrome P450 Active Site: Structural Insights into Human CYP2B6 Substrate Selectivity.ACS chemical biology · 2017Article
- Synthesis and biological evaluation of novel hybrids of highly potent and selective α4β2-Nicotinic acetylcholine receptor (nAChR) partial agonists.European journal of medicinal chemistry · 2016Article
- From deep TLS validation to ensembles of atomic models built from elemental motions.Acta crystallographica. Section D, Biological crystallography · 2015Article
- Varenicline Interactions at the 5-HT3 Receptor Ligand Binding Site are Revealed by 5-HTBP.ACS chemical neuroscience · 2015Article
- Recent developments in novel antidepressants targeting α4β2-nicotinic acetylcholine receptors.Journal of medicinal chemistry · 2014Review
- Structural and functional studies of the modulator NS9283 reveal agonist-like mechanism of action at α4β2 nicotinic acetylcholine receptors.The Journal of biological chemistry · 2014Article
- Probing the orthosteric binding site of GABAA receptors with heterocyclic GABA carboxylic acid bioisosteres.Neurochemical research · 2014Review
- Probing the non-canonical interface for agonist interaction with an α5 containing nicotinic acetylcholine receptor.Neuropharmacology · 2014Article
- Article
- Two distinct allosteric binding sites at α4β2 nicotinic acetylcholine receptors revealed by NS206 and NS9283 give unique insights to binding activity-associated linkage at Cys-loop receptors.The Journal of biological chemistry · 2013Article
- Covalent trapping of methyllycaconitine at the α4-α4 interface of the α4β2 nicotinic acetylcholine receptor: antagonist binding site and mode of receptor inhibition revealed.The Journal of biological chemistry · 2013Article
- An unusual pattern of ligand-receptor interactions for the α7 nicotinic acetylcholine receptor, with implications for the binding of varenicline.Molecular pharmacology · 2013Article
- Molecular determinants of subtype-selective efficacies of cytisine and the novel compound NS3861 at heteromeric nicotinic acetylcholine receptors.The Journal of biological chemistry · 2013Article
- A unified model of the GABA(A) receptor comprising agonist and benzodiazepine binding sites.PloS one · 2013Article
- Crystal structure of Lymnaea stagnalis AChBP complexed with the potent nAChR antagonist DHβE suggests a unique mode of antagonism.PloS one · 2012Article
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Authors and funding
11 authors at 2 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
The α4β2 subtype of the nicotinic acetylcholine receptor has been pursued as a drug target for treatment of psychiatric and neurodegenerative disorders and smoking cessation aids for decades. Still, a thorough understanding of structure-function relationships of α4β2 agonists is lacking. Using binding experiments, electrophysiology and x-ray crystallography we have investigated a consecutive series of five prototypical pyridine-containing agonists derived from 1-(pyridin-3-yl)-1,4-diazepane. A correlation between binding affinities at α4β2 and the acetylcholine-binding protein from Lymnaea stagnalis (Ls-AChBP) confirms Ls-AChBP as structural surrogate for α4β2 receptors. Crystal structures of five agonists with efficacies at α4β2 from 21-76% were determined in complex with Ls-AChBP. No variation in closure of loop C is observed despite large efficacy variations. Instead, the efficacy of a compound appears tightly coupled to its ability to form a strong intersubunit bridge linking the primary and complementary binding interfaces. For the tested agonists, a specific halogen bond was observed to play a large role in establishing such strong intersubunit anchoring.
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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.