{
  "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.",
  "abstract_shown": true,
  "affiliations": [
    "Department of Chemistry, Chemistry Research Laboratory, University of Oxford, Mansfield Road, Oxford, UK.",
    "Department of Pharmacology, University of Oxford, Mansfield Road, Oxford, UK.",
    "Shanghai Academy of Artificial Intelligence for Science, Shanghai, China.",
    "Department of Pharmacology and Chemical Biology, School of Medicine, University of Pittsburgh, Pittsburgh, PA, USA.",
    "School of Pharmacy, Queen's University Belfast, Belfast, Northern Ireland, UK.",
    "School of Molecular Biosciences, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, UK.",
    "Department of Biochemistry, University of Oxford, South Parks Road, Oxford, UK.",
    "Sir William Dunn School of Pathology, University of Oxford, South Parks Road, Oxford, UK.",
    "School of Molecular Biosciences, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, UK. Graeme.Milligan@glasgow.ac.uk.",
    "Department of Pharmacology and Chemical Biology, School of Medicine, University of Pittsburgh, Pittsburgh, PA, USA. chengzh@pitt.edu.",
    "School of Pharmacy, Queen's University Belfast, Belfast, Northern Ireland, UK. i.tikhonova@qub.ac.uk.",
    "Department of Chemistry, Chemistry Research Laboratory, University of Oxford, Mansfield Road, Oxford, UK. angela.russell@chem.ox.ac.uk.",
    "Department of Pharmacology, University of Oxford, Mansfield Road, Oxford, UK. angela.russell@chem.ox.ac.uk."
  ],
  "article_type": "research support, non u.s. gov't",
  "arxiv": null,
  "author_total": 17,
  "authors": [
    {
      "affs": [
        0,
        1,
        2
      ],
      "name": "Pinqi Wang",
      "orcid": "0009-0007-1160-1206"
    },
    {
      "affs": [
        3
      ],
      "name": "Xuan Zhang",
      "orcid": "0000-0002-4276-6464"
    },
    {
      "affs": [
        4,
        5
      ],
      "name": "Abdul-Akim Guseinov",
      "orcid": "0000-0002-2796-4323"
    },
    {
      "affs": [
        5
      ],
      "name": "Laura Jenkins"
    },
    {
      "affs": [
        6
      ],
      "name": "Carl von Hallerstein",
      "orcid": "0009-0003-6608-3603"
    },
    {
      "affs": [
        6
      ],
      "name": "Jonathan D Colburn"
    },
    {
      "affs": [
        0,
        1,
        7
      ],
      "name": "Rowan Ives",
      "orcid": "0009-0008-6353-3935"
    },
    {
      "affs": [
        7
      ],
      "name": "Vincent B Luscombe"
    },
    {
      "affs": [
        5
      ],
      "name": "Sara Marsango"
    },
    {
      "affs": [
        0,
        1
      ],
      "name": "Listiana Oktavia"
    },
    {
      "affs": [
        0,
        1
      ],
      "name": "Arun Raja"
    },
    {
      "affs": [
        7
      ],
      "name": "David R Greaves",
      "orcid": "0000-0003-2856-9410"
    },
    {
      "affs": [
        6
      ],
      "name": "Philip C Biggin",
      "orcid": "0000-0001-5100-8836"
    },
    {
      "affs": [
        8
      ],
      "name": "Graeme Milligan",
      "orcid": "0000-0002-6946-3519"
    },
    {
      "affs": [
        9
      ],
      "name": "Cheng Zhang",
      "orcid": "0000-0001-9042-4007"
    },
    {
      "affs": [
        10
      ],
      "name": "Irina G Tikhonova",
      "orcid": "0000-0002-6228-9431"
    },
    {
      "affs": [
        11,
        12
      ],
      "name": "Angela J Russell",
      "orcid": "0000-0003-3610-9369"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/932w0sqtrfeqn.bib",
  "cited_by": 3,
  "doi": "10.1038/s41467-026-77312-7",
  "fulltext_url": "https://europepmc.org/articles/PMC13642346",
  "id": "932w0sqtrfeqn",
  "issns": [
    "2041-1723"
  ],
  "landing_url": "https://europepmc.org/article/MED/42838941",
  "language": "eng",
  "licence": "CC-BY",
  "licence_label": "CC BY",
  "licence_source": "article",
  "licence_url": "https://creativecommons.org/licenses/by/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "openalex",
      "1312|Receptor Mechanisms and Signaling"
    ]
  ],
  "openalex": "W4412854962",
  "pdf_url": "https://europepmc.org/articles/PMC13642346?pdf=render",
  "pmcid": "PMC13642346",
  "pmid": "42838941",
  "published": "2026-09-05",
  "publisher": null,
  "ris": "https://research.draconitic.com/paper/932w0sqtrfeqn.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T12:18:10Z",
      "native_id": "MED:42838941",
      "source": "europepmc",
      "url": "https://europepmc.org/article/MED/42838941"
    }
  ],
  "subjects": [
    {
      "field": "biochemistry",
      "origin": "openalex:1312|Receptor Mechanisms and Signaling",
      "subfield": "molecular-biology"
    }
  ],
  "title": "Steric control of signaling bias in the immunometabolic receptor GPR84.",
  "title_text": "Steric control of signaling bias in the immunometabolic receptor GPR84.",
  "type": "peer-reviewed",
  "updated_at": "2026-10-30T12:18:10Z",
  "url": "https://research.draconitic.com/paper/932w0sqtrfeqn",
  "venue": "Nature communications",
  "versions": []
}