Researchers mapped the molecular mechanism controlling signaling bias in the immunometabolic receptor GPR84, according to a peer-reviewed study published Sept. 5, 2026, in Nature Communications. The team identified three structurally matched ligands—designated OX04529, OX04954, and OX04539—that possess differing steric profiles while triggering comparable Gi protein activation alongside markedly different β-arrestin recruitment capacities.
Investigators captured a high-resolution cryo-electron microscopy structure of GPR84-Gi complexed with OX04529, combining the structural data with molecular dynamics simulations and targeted mutagenesis. The tests showed that steric interactions between ligand substituents and residues Leu3366.52 and Phe1875.47 indirectly disrupt a polar network involving Tyr3326.48, Asn1043.36, and Asn3627.45. Disruption of this polar network impairs β-arrestin recruitment.
The team used these structural insights to build a steric-dependent model for rationally designing G protein-biased agonists with predictable β-arrestin recruitment profiles. The authors reported that the mechanistic framework offers a means to design biased agonists with customized signaling profiles at GPR84 and potentially across other class A G protein-coupled receptors.
Five co-lead authors—Pinqi Wang, Xuan Zhang, Abdul-Akim Guseinov, Laura Jenkins, and Carl von Hallerstein—conducted the research across the University of Oxford, Queen’s University Belfast, the University of Glasgow, and the University of Pittsburgh. Computational simulations ran on the Kelvin-2 supercomputer and the ARCHER2 service through the UK High-End Computing Consortium for Biomolecular Simulation. Imaging data collection took place at the Pittsburgh Center for CryoEM.
The journal originally received the manuscript on Aug. 27, 2025, and accepted it on Aug. 10, 2026. Financial support included grants from the Biotechnology and Biological Sciences Research Council, the Wellcome Trust, the British Heart Foundation, the European Union’s Horizon 2020 program, Merck Sharp and Dohme Corp., and Janssen Pharmaceutica NV.
