Receptor Mechanisms and Signaling
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Abstract
Abstract
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.
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@article{Wang2026Steric,
title = {Steric control of signaling bias in the immunometabolic receptor GPR84},
author = {Pinqi Wang and Xuan Zhang and A. -K. Guseinov and Laura Jenkins and Carl von Hallerstein and Jonathan D. Colburn 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},
doi = {10.1038/s41467-026-77312-7},
url = {https://doi.org/10.1038/s41467-026-77312-7}
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