ArticleThe Journal of biological chemistry2011
Ligand modulation of the Epstein-Barr virus-induced seven-transmembrane receptor EBI2: identification of a potent and efficacious inverse agonist.
Article in The Journal of biological chemistry, 2011. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 30 papers.
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Who cites it
30 citing papers in PubMed, 49 citations in OpenAlex.
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- Structure-based screening and a conformational biosensor identify a GPR183 inverse agonist and an activation switch.Nature communications · 2026Article
- GPR183-mediated immune cell positioning and function: an integrative perspective across ligand gradients, tissue environments, and disease stages.Frontiers in immunology · 2026Review
- Diabetes exacerbates myasthenia gravis by enhancing pathological thymic output via the GPR183-7α,25-OHC axis.Journal of neuroinflammation · 2025Article
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- First report on chemometrics-driven multilayered lead prioritization in addressing oxysterol-mediated overexpression of G protein-coupled receptor 183.Molecular diversity · 2024Article
- Sexual Dimorphism in the Immunometabolic Role of Gpr183 in Mice.Journal of the Endocrine Society · 2024Article
- The role of orphan G protein-coupled receptors in pain.Heliyon · 2024Review
- Ligand entry pathways control the chemical space recognized by GPR183.Chemical science · 2023Article
- Activation of GPR183 by 7The Journal of pharmacology and experimental therapeutics · 2022Article
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- Discovery of GPR183 Agonists Based on an Antagonist Scaffold.ChemMedChem · 2021Article
- GPR183-Oxysterol Axis in Spinal Cord Contributes to Neuropathic Pain.The Journal of pharmacology and experimental therapeutics · 2020Article
- Integrated, multicohort analysis reveals unified signature of systemic lupus erythematosus.JCI insight · 2020Article
- GPR183 Regulates Interferons, Autophagy, and Bacterial Growth DuringFrontiers in immunology · 2020Article
- Arrestin-independent constitutive endocytosis of GPR125/ADGRA3.Annals of the New York Academy of Sciences · 2019Article
- Oxysterols in intestinal immunity and inflammation.Journal of internal medicine · 2019Review
- Cholesterol metabolism promotes B-cell positioning during immune pathogenesis of chronic obstructive pulmonary disease.EMBO molecular medicine · 2018Article
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Authors and funding
10 authors at 3 institutions in 3 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
The Epstein-Barr virus-induced receptor 2 (EBI2) is a constitutively active seven-transmembrane receptor, which was recently shown to orchestrate the positioning of B cells in the follicle. To date, no ligands, endogenously or synthetic, have been identified that modulate EBI2 activity. Here we describe an inverse agonist, GSK682753A, which selectively inhibited the constitutive activity of EBI2 with high potency and efficacy. In cAMP-response element-binding protein-based reporter and guanosine 5'-3-O-(thio)triphosphate (GTPγS) binding assays, the potency of this compound was 2.6-53.6 nm, and its inhibitory efficacy was 75%. In addition, we show that EBI2 constitutively activated extracellular signal-regulated kinase (ERK) in a pertussis toxin-insensitive manner. Intriguingly, GSK682753A inhibited ERK phosphorylation, GTPγS binding, and cAMP-response element-binding protein activation with similar potency. Overexpression of EBI2 profoundly potentiated antibody-stimulated ex vivo proliferation of murine B cells compared with WT cells, whereas this was equivalently reduced for EBI2-deficient B cells. Inhibition of EBI2 constitutive activity suppressed the proliferation in all cases. Importantly, the suppression was of much higher potency (32-fold) in WT or EBI2-overexpressing B cells compared with EBI2-deficient counterparts. Finally, we screened GSK682753A against an EBI2 mutant library to determine putative molecular binding determinants in EBI2. We identified Phe(111) at position III:08/3.32 as being crucial for GSK682753A inverse agonism because Ala substitution resulted in a >500-fold decrease in IC(50). In conclusion, we present the first ligand targeting EBI2. In turn, this molecule provides a useful tool for further characterization of EBI2 as well as serving as a potent lead compound.
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