ArticleProceedings of the National Academy of Sciences of the United States of America2012
Molecular actions of smoking cessation drugs at α4β2 nicotinic receptors defined in crystal structures of a homologous binding protein.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 32 papers.
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Who cites it
32 citing papers in PubMed, 67 citations in OpenAlex.
- Understanding varenicline function via key receptor and ligand interactions.Cell reports. Physical science · 2025Article
- Pharmacophore Mapping Combined with dbCICA Reveal New Structural Features for the Development of Novel Ligands Targeting α4β2 and α7 Nicotinic Acetylcholine Receptors.Molecules (Basel, Switzerland) · 2022Article
- Delineating the activity of the potent nicotinic acetylcholine receptor agonists (+)-anatoxin-a and (-)-hosieine-A.Acta crystallographica. Section F, Structural biology communications · 2022Article
- Interactions between 2'-fluoro-(carbamoylpyridinyl)deschloroepibatidine analogues and acetylcholine-binding protein inform on potent antagonist activity against nicotinic receptors.Acta crystallographica. Section D, Structural biology · 2022Article
- Discovery of fragments inducing conformational effects in dynamic proteins using a second-harmonic generation biosensor.RSC advances · 2021Article
- Beyond Alkaloids: Novel Bioactive Natural Products FromFrontiers in pharmacology · 2021Review
- Attenuating nicotine's effects with high affinity human anti-nicotine monoclonal antibodies.PloS one · 2021Article
- Orthosteric and Allosteric Activation of Human 5-HTBiophysical journal · 2020Article
- Synthetic antibodies against BRIL as universal fiducial marks for single-particle cryoEM structure determination of membrane proteins.Nature communications · 2020Article
- The thermodynamic profile and molecular interactions of a C(9)-cytisine derivative-binding acetylcholine-binding protein from Aplysia californica.Acta crystallographica. Section F, Structural biology communications · 2020Article
- An allosteric binding site of the α7 nicotinic acetylcholine receptor revealed in a humanized acetylcholine-binding protein.The Journal of biological chemistry · 2018Article
- Escherichia coli Protein Expression System for Acetylcholine Binding Proteins (AChBPs).PloS one · 2016Article
- Article
- Varenicline Interactions at the 5-HT3 Receptor Ligand Binding Site are Revealed by 5-HTBP.ACS chemical neuroscience · 2015Article
- Nicotinic ACh receptors as therapeutic targets in CNS disorders.Trends in pharmacological sciences · 2015Review
- The binding characteristics and orientation of a novel radioligand with distinct properties at 5-HT3A and 5-HT3AB receptors.Neuropharmacology · 2014Article
- Recent developments in novel antidepressants targeting α4β2-nicotinic acetylcholine receptors.Journal of medicinal chemistry · 2014Review
- Real time ligand-induced motion mappings of AChBP and nAChR using X-ray single molecule tracking.Scientific reports · 2014Article
- Functional probes of drug-receptor interactions implicated by structural studies: Cys-loop receptors provide a fertile testing ground.Journal of medicinal chemistry · 2014Review
- Non-equivalent ligand selectivity of agonist sites in (α4β2)2α4 nicotinic acetylcholine receptors: a key determinant of agonist efficacy.The Journal of biological chemistry · 2014Article
Corrections and comments
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Authors and funding
10 authors at 4 institutions in 4 countries.
Funding
Abstract
Partial agonists of the α4β2 nicotinic acetylcholine receptor (nAChR), such as varenicline, are therapeutically used in smoking cessation treatment. These drugs derive their therapeutic effect from fundamental molecular actions, which are to desensitize α4β2 nAChRs and induce channel opening with higher affinity, but lower efficacy than a full agonist at equal receptor occupancy. Here, we report X-ray crystal structures of a unique acetylcholine binding protein (AChBP) from the annelid Capitella teleta, Ct-AChBP, in complex with varenicline or lobeline, which are both partial agonists. These structures highlight the architecture for molecular recognition of these ligands, indicating the contact residues that potentially mediate their molecular actions in α4β2 nAChRs. We then used structure-guided mutagenesis and electrophysiological recordings to pinpoint crucial interactions of varenicline with residues on the complementary face of the binding site in α4β2 nAChRs. We observe that residues in loops D and E are molecular determinants of desensitization and channel opening with limited efficacy by the partial agonist varenicline. Together, this study analyzes molecular recognition of smoking cessation drugs by nAChRs in a structural context.
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