Steric control of signaling bias in the immunometabolic receptor GPR84
Abstract 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.
Authors
- Angela J. Russell (ORCID: https://orcid.org/0000-0003-3610-9369)
- Arun Raja (ORCID: https://orcid.org/0000-0002-4060-2490)
- Listiana Oktavia (ORCID: https://orcid.org/0000-0002-8664-4506)
- Pinqi Wang (ORCID: https://orcid.org/0009-0007-1160-1206)
- Philip C. Biggin (ORCID: https://orcid.org/0000-0001-5100-8836)
- Jonathan D. Colburn (ORCID: https://orcid.org/0000-0001-9613-1045)
- Graeme Milligan (ORCID: https://orcid.org/0000-0002-6946-3519)
- Irina G. Tikhonova (ORCID: https://orcid.org/0000-0002-6228-9431)
- Sara Marsango (ORCID: https://orcid.org/0000-0002-0590-7942)
- Vincent B. Luscombe (ORCID: https://orcid.org/0000-0002-2886-4017)
- David R. Greaves (ORCID: https://orcid.org/0000-0003-2856-9410)
- Laura Jenkins (ORCID: https://orcid.org/0000-0002-7259-4448)
- Xuan Zhang (ORCID: https://orcid.org/0000-0002-4999-7361)
- Cheng Zhang (ORCID: https://orcid.org/0000-0003-2663-4207)
- A. -K. Guseinov
- Carl von Hallerstein
Institutions
- Queen's University Belfast (GB)
- Mansfield University (US)
- University of Pittsburgh (US)
- Oxford Research Group (GB)
- University of Oxford (GB)
- University of Glasgow (GB)
Publication Details
- Journal
- Nature Communications
- Published
- 2026-09-05
- DOI
- https://doi.org/10.1038/s41467-026-77312-7
- Citations
- 1
- Primary Topic
- Receptor Mechanisms and Signaling
- Type
- article
- Field-Weighted Citation Impact
- 2.87
Funders
- University of Pittsburgh
- Wellcome Trust
- British Heart Foundation
- European Commission
- Lembaga Pengelola Dana Pendidikan
- National Institutes of Health
- Directorate for Biological Sciences
- Engineering and Physical Sciences Research Council
- Biotechnology and Biological Sciences Research Council
- Clarendon Fund