Steric control of signaling bias in the immunometabolic receptor GPR84
- Pinqi Wang
- Xuan Zhang
- Abdul-Akim Guseinov
- Laura Jenkins
- Carl von Hallerstein
- Jonathan D. Colburn
- Rowan Ives
- Vincent B. Luscombe
- Sara Marsango
- Listiana Oktavia
- Arun Raja
- David R. Greaves
- Philip C. Biggin
- Graeme Milligan
- Cheng Zhang
- Irina G. Tikhonova
- Angela J. Russell
2026-09-05
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 G i protein activation but markedly different β-arrestin recruitment capacities. A high-resolution cryo-EM structure of GPR84-G i in complex with OX04529, complemented by molecular dynamics simulations and targeted mutagenesis, reveals that steric interactions between ligand substituents and Leu336 6.52 and Phe187 5.47 indirectly disrupt a critical polar network involving Tyr332 6.48 , Asn104 3.36 and Asn362 7.45 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.