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<p>GPR183 is a chemotactic GPCR involved in immune cell migration. Using AI-driven virtual screening and biophysical assays, we identify inverse agonists. From 70 compounds and a subsequent hit expansion, compound 78 emerges as a potent inhibitor of constitutive and agonist-induced Gi signaling as well as β-arrestin2 recruitment. Binding within the receptor core is confirmed by a conformational biosensor, molecular dynamics simulations, and mutagenesis. The compound also blocks agonist-driven migration of peripheral blood mononuclear cells ex vivo with very high potency. Additionally, our analyses reveal key features of GPR183 activation, highlighting tyrosine 260 (Y260<sup>6.51</sup>) in transmembrane helix 6 as critical. Mutation of this residue alters compound 78 efficacy as well as induces receptor signaling bias, indicating a switch mechanism. Overall, this study provides tools to probe GPR183 function, identifies a chemical scaffold, and advances understanding of receptor activation, supporting therapeutic targeting in inflammatory, autoimmune, and cancer-related diseases.</p>

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Structure-based screening and a conformational biosensor identify a GPR183 inverse agonist and an activation switch

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年5月30日

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  • Louise Andersson,
  • Michele Roggia,
  • Kittikorn Wangriatisak,
  • Rhiannon Skye Kozel,
  • Holly R. Brittain,
  • Sonia Youhanna,
  • Maria Gil,
  • Mathias Haag,
  • Volker M. Lauschke,
  • Karine Chemin,
  • Sandro Cosconati,
  • Paweł Kozielewicz

摘要

GPR183 is a chemotactic GPCR involved in immune cell migration. Using AI-driven virtual screening and biophysical assays, we identify inverse agonists. From 70 compounds and a subsequent hit expansion, compound 78 emerges as a potent inhibitor of constitutive and agonist-induced Gi signaling as well as β-arrestin2 recruitment. Binding within the receptor core is confirmed by a conformational biosensor, molecular dynamics simulations, and mutagenesis. The compound also blocks agonist-driven migration of peripheral blood mononuclear cells ex vivo with very high potency. Additionally, our analyses reveal key features of GPR183 activation, highlighting tyrosine 260 (Y2606.51) in transmembrane helix 6 as critical. Mutation of this residue alters compound 78 efficacy as well as induces receptor signaling bias, indicating a switch mechanism. Overall, this study provides tools to probe GPR183 function, identifies a chemical scaffold, and advances understanding of receptor activation, supporting therapeutic targeting in inflammatory, autoimmune, and cancer-related diseases.