What does this research mean for the field?

Compound 78 is a potent GPR183 inverse agonist that blocks agonist-driven immune cell migration, and tyrosine 260 (Y260) serves as a critical activation switch for the receptor's signaling. Novelty: ClaimNovelty.NOVEL_FINDING. Consensus alignment: ConsensusAlignment.NEUTRAL.

What question did this study set out to answer?

To identify inverse agonists for GPR183 and understand the mechanism of receptor activation.

June 1, 2026Nature Communications0 citationsOpen Access

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

LALouise Andersson MRMichele Roggia KWKittikorn Wangriatisak

Key Points

To identify inverse agonists for GPR183 and understand the mechanism of receptor activation.
Used AI-driven virtual screening of 70 compounds to find inhibitors.
Conducted biophysical assays, including molecular dynamics simulations and mutagenesis, to confirm compound functionality.
Analyzed the effect of compound 78 on immune cell migration and receptor signaling bias.
Compound 78 inhibits Gi signaling and β-arrestin2 recruitment, with confirmed binding in the GPR183 receptor core.
It blocks agonist-driven migration of peripheral blood mononuclear cells with very high potency.
Mutation of tyrosine 260 alters compound 78 efficacy and induces receptor signaling bias.

Abstract

Abstract 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 6.51 ) 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.

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