{
  "abstract": "G protein-coupled receptors (GPCRs) regulate diverse physiological responses by engaging distinct heterotrimeric G proteins, yet the basis of G selectivity in promiscuous receptors remains unclear. Although ligand bias holds therapeutic promise, selectivity has been assumed to reside mainly in the ligand-binding site (LBS) or G protein interface (GPI). Here, we combine whole-receptor mutagenesis, functional G protein assays, molecular dynamics simulations, interpretable machine learning method, and Bayesian network modeling to identify residue networks governing Gq/11 and G12/13 coupling and to define the molecular basis of G protein preference and promiscuity at two vasopressor GPCRs, the angiotensin II type 1 and prostaglandin F2 receptors. While residues within the LBS and GPI domains contribute to coupling efficiency and subtype discrimination, we find that long-range allosteric communication across the receptor, including from structurally unresolved domains, is the principal determinant of G protein preference and promiscuity. These allosteric pathways integrate multiple receptor domains, confer signaling robustness to mutation, and hierarchically govern coupling preferences. Our findings suggest that G protein selectivity is an allosterically encoded property of GPCRs and provide a conceptual framework for designing ligands and receptors with tailored G protein-biased signaling.",
  "abstract_shown": true,
  "affiliations": [
    "Research Institute of the McGill University Health Centre"
  ],
  "article_type": "New results",
  "arxiv": null,
  "author_total": 12,
  "authors": [
    {
      "name": "T. S. Boora"
    },
    {
      "name": "H. Chen"
    },
    {
      "name": "A. Cho"
    },
    {
      "name": "W. J. C. van der Velden"
    },
    {
      "name": "Y. Namkung"
    },
    {
      "name": "Y. Cao"
    },
    {
      "name": "J. Y. Paranjpe"
    },
    {
      "name": "F. M. Heydenreich"
    },
    {
      "name": "A. S. RODIN"
    },
    {
      "name": "S. Branciamore"
    },
    {
      "name": "N. Vaidehi"
    },
    {
      "affs": [
        0
      ],
      "name": "S. Laporte"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/29e8e8n790qtb.bib",
  "cited_by": 0,
  "doi": "10.64898/2026.08.28.747882",
  "fulltext_url": "https://www.biorxiv.org/content/10.64898/2026.08.28.747882v1.full",
  "id": "29e8e8n790qtb",
  "issns": [],
  "landing_url": "https://www.biorxiv.org/content/10.64898/2026.08.28.747882v1",
  "language": null,
  "licence": "CC-BY-NC",
  "licence_label": "CC BY-NC",
  "licence_source": "article",
  "licence_url": "https://creativecommons.org/licenses/by-nc/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "biorxiv",
      "pharmacology and toxicology"
    ],
    [
      "openalex",
      "1312|Receptor Mechanisms and Signaling"
    ]
  ],
  "openalex": "W7208785616",
  "pdf_url": "https://www.biorxiv.org/content/10.64898/2026.08.28.747882v1.full.pdf",
  "pmcid": null,
  "pmid": null,
  "published": "2026-08-28",
  "publisher": null,
  "ris": "https://research.draconitic.com/paper/29e8e8n790qtb.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T12:19:14Z",
      "native_id": "10.64898/2026.08.28.747882",
      "source": "biorxiv",
      "url": "https://www.biorxiv.org/content/10.64898/2026.08.28.747882v1"
    }
  ],
  "subjects": [
    {
      "field": "medicine",
      "origin": "biorxiv:pharmacology and toxicology",
      "subfield": "pharmacology-toxicology"
    }
  ],
  "title": "Allosteric pathways govern Gα protein coupling selectivity at promiscuous GPCRs",
  "title_text": "Allosteric pathways govern Gα protein coupling selectivity at promiscuous GPCRs",
  "type": "preprint",
  "updated_at": "2026-10-30T12:19:14Z",
  "url": "https://research.draconitic.com/paper/29e8e8n790qtb",
  "venue": "bioRxiv",
  "versions": []
}