ArticleInternational immunopharmacology2011
Mutagenesis and computer modeling studies of a GPCR conserved residue W5.43(194) in ligand recognition and signal transduction for CB2 receptor.
Article in International immunopharmacology, 2011. 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, 24 citations in OpenAlex.
- Candidate Therapeutics by Screening for Multitargeting Ligands: Combining the CB2 Receptor With CB1, PPARγ and 5-HT4 Receptors.Frontiers in pharmacology · 2022Article
- Xie2-64, a novel CBNeuropharmacology · 2020Article
- Article
- Negative allosteric modulators of cannabinoid receptor 2: protein modeling, binding site identification and molecular dynamics simulations in the presence of an orthosteric agonist.Journal of biomolecular structure & dynamics · 2020Article
- Selective Cannabinoid 2 Receptor Stimulation Reduces Tubular Epithelial Cell Damage after Renal Ischemia-Reperfusion Injury.The Journal of pharmacology and experimental therapeutics · 2018Article
- Multi-Functional Diarylurea Small Molecule Inhibitors of TRPV1 with Therapeutic Potential for Neuroinflammation.The AAPS journal · 2016Article
- Difference and Influence of Inactive and Active States of Cannabinoid Receptor Subtype CB2: From Conformation to Drug Discovery.Journal of chemical information and modeling · 2016Article
- Targeting cannabinoid receptor-2 pathway by phenylacetylamide suppresses the proliferation of human myeloma cells through mitotic dysregulation and cytoskeleton disruption.Molecular carcinogenesis · 2015Article
- CB2 cannabinoid receptor agonist enantiomers HU-433 and HU-308: An inverse relationship between binding affinity and biological potency.Proceedings of the National Academy of Sciences of the United States of America · 2015Article
- Ligand biological activity predictions using fingerprint-based artificial neural networks (FANN-QSAR).Methods in molecular biology (Clifton, N.J.) · 2015Article
- Examining the critical roles of human CB2 receptor residues Valine 3.32 (113) and Leucine 5.41 (192) in ligand recognition and downstream signaling activities.Biochemical and biophysical research communications · 2014Article
- Modeling, molecular dynamics simulation, and mutation validation for structure of cannabinoid receptor 2 based on known crystal structures of GPCRs.Journal of chemical information and modeling · 2014Article
- Receptor binding peptides for target-selective delivery of nanoparticles encapsulated drugs.International journal of nanomedicine · 2014Review
- Mastering tricyclic ring systems for desirable functional cannabinoid activity.European journal of medicinal chemistry · 2013Article
- The importance of hydrogen bonding and aromatic stacking to the affinity and efficacy of cannabinoid receptor CB2 antagonist, 5-(4-chloro-3-methylphenyl)-1-[(4-methylphenyl)methyl]-N-[(1S,2S,4R)-1,3,3-trimethylbicyclo[2.2.1]hept-2-yl]-1H-pyrazole-3-carboxamide (SR144528).Journal of medicinal chemistry · 2013Article
- Trisubstituted Sulfonamides: a New Chemotype for Development of Potent and Selective CBACS medicinal chemistry letters · 2013Article
- Novel triaryl sulfonamide derivatives as selective cannabinoid receptor 2 inverse agonists and osteoclast inhibitors: discovery, optimization, and biological evaluation.Journal of medicinal chemistry · 2013Article
- Lead discovery, chemistry optimization, and biological evaluation studies of novel biamide derivatives as CB2 receptor inverse agonists and osteoclast inhibitors.Journal of medicinal chemistry · 2012Article
- Molecular fingerprint-based artificial neural networks QSAR for ligand biological activity predictions.Molecular pharmaceutics · 2012Article
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Authors and funding
7 authors at 3 institutions in 2 countries.
Funding
Abstract
W5.43(194), a conserved tryptophan residue among G-protein coupled receptors (GPCRs) and cannabinoid receptors (CB), was examined in the present report for its significance in CB2 receptor ligand binding and adenylyl cyclase (AC) activity. Computer modeling postulates that this site in CB2 may be involved in the affinity of WIN55212-2 and SR144528 through aromatic contacts. In the present study, we reported that a CB2 receptor mutant, W5.43(194)Y, which had a tyrosine (Y) substitution for tryptophan (W), retained the binding affinity for CB agonist CP55940, but reduced binding affinity for CB2 agonist WIN55212-2 and inverse agonist SR144528 by 8-fold and 5-fold, respectively; the CB2 W5.43(194)F and W5.43(194)A mutations significantly affect the binding activities of CP55940, WIN55212-2 and SR144528. Furthermore, we found that agonist-mediated inhibition of the forskolin-induced cAMP production was dramatically diminished in the CB2 mutant W5.43(194)Y, whereas W5.43(194)F and W5.43(194)A mutants resulted in complete elimination of downstream signaling, suggesting that W5.43(194) was essential for the full activation of CB2. These results indicate that both aromatic interaction and hydrogen bonding are involved in ligand binding for the residue W5.43(194), and the mutations of this tryptophan site may affect the conformation of the ligand binding pocket and therefore control the active conformation of the wild type CB2 receptor. W5.43(194)Y/F/A mutations also displayed noticeable enhancement of the constitutive activation probably attributed to the receptor conformational changes resulted from the mutations.
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