Steric control of signaling bias in the immunometabolic receptor GPR84

Journal article

Biased signaling in G protein-coupled receptors offers therapeutic promise, yet rational design of biased ligands remains challenging due to limited mechanistic understanding. Here, we report a molecular basis for controlling signaling bias at the immunometabolic receptor GPR84. We identify three structurally-matched ligands (OX04529, OX04954, and OX04539) with varying steric profiles that exhibit comparable Gi protein activation but markedly different β-arrestin recruitment capacities. A high-resolution cryo-EM structure of GPR84-Gi in complex with OX04529, complemented by molecular dynamics simulations and targeted mutagenesis, reveals that steric interactions between ligand substituents and Leu3366.52 and Phe1875.47 indirectly disrupt a critical polar network involving Tyr3326.48, Asn1043.36 and Asn3627.45 essential for β-arrestin recruitment. Based on these insights, we develop a steric-dependent model that enables rational design of G protein-biased agonists with predictable β-arrestin recruitment profiles. This mechanistic framework provides the means to design biased agonists with customized signaling profiles at GPR84 and potentially other class A GPCRs.

Authors: Wang, P; Zhang, X; Guseinov, A-A; Jenkins, L; von Hallerstein, C

• Publication status: Published
• Peer review status: Peer reviewed
• Publisher: Nature Research
• Journal: Nature Communications
• Volume: 17
• Issue: 1
• Publication date: 2026-09-05
• Acceptance date: 2026-08-10
• DOI: 10.1038/s41467-026-77312-7
• EISSN: 2041-1723
• ISSN: 2041-1723
• Language: English
• Keywords: ligand design; β-arrestin recruitment; G protein signaling; class A GPCRs; biased agonists; GPR84; cryo-EM structure; steric interactions; G protein-coupled receptors