Steric control of signaling bias in the immunometabolic receptor GPR84.
13 affiliations
- 1Department of Chemistry, Chemistry Research Laboratory, University of Oxford, Mansfield Road, Oxford, UK.
- 2Department of Pharmacology, University of Oxford, Mansfield Road, Oxford, UK.
- 3Shanghai Academy of Artificial Intelligence for Science, Shanghai, China.
- 4Department of Pharmacology and Chemical Biology, School of Medicine, University of Pittsburgh, Pittsburgh, PA, USA.
- 5School of Pharmacy, Queen's University Belfast, Belfast, Northern Ireland, UK.
- 6School of Molecular Biosciences, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, UK.
- 7Department of Biochemistry, University of Oxford, South Parks Road, Oxford, UK.
- 8Sir William Dunn School of Pathology, University of Oxford, South Parks Road, Oxford, UK.
- 9School of Molecular Biosciences, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, UK. [email protected].
- 10Department of Pharmacology and Chemical Biology, School of Medicine, University of Pittsburgh, Pittsburgh, PA, USA. [email protected].
- 11School of Pharmacy, Queen's University Belfast, Belfast, Northern Ireland, UK. [email protected].
- 12Department of Chemistry, Chemistry Research Laboratory, University of Oxford, Mansfield Road, Oxford, UK. [email protected].
- 13Department of Pharmacology, University of Oxford, Mansfield Road, Oxford, UK. [email protected].
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 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.
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BibTeX
@article{wang2026steric,
title = {{Steric control of signaling bias in the immunometabolic receptor GPR84.}},
author = {Pinqi Wang and Xuan Zhang and Abdul-Akim Guseinov and Laura Jenkins and Carl von Hallerstein and Jonathan D Colburn and Rowan Ives and Vincent B Luscombe and Sara Marsango and Listiana Oktavia and Arun Raja and David R Greaves and Philip C Biggin and Graeme Milligan and Cheng Zhang and Irina G Tikhonova and Angela J Russell},
journal = {Nature communications},
year = {2026},
month = sep,
doi = {10.1038/s41467-026-77312-7},
url = {https://europepmc.org/article/MED/42838941},
note = {CC BY},
}
RIS
TY - JOUR
TI - Steric control of signaling bias in the immunometabolic receptor GPR84.
AU - Pinqi Wang
AU - Xuan Zhang
AU - Abdul-Akim Guseinov
AU - Laura Jenkins
AU - Carl von Hallerstein
AU - Jonathan D Colburn
AU - Rowan Ives
AU - Vincent B Luscombe
AU - Sara Marsango
AU - Listiana Oktavia
AU - Arun Raja
AU - David R Greaves
AU - Philip C Biggin
AU - Graeme Milligan
AU - Cheng Zhang
AU - Irina G Tikhonova
AU - Angela J Russell
PY - 2026
DA - 2026/09/05
JO - Nature communications
DO - 10.1038/s41467-026-77312-7
UR - https://europepmc.org/article/MED/42838941
AB - 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.
SN - 2041-1723
ER -