{
  "abstract": "Biased signaling of G protein-coupled receptors (GPCRs) offers a route for precise therapeutics with fewer adverse effects. Intracellular allosteric ligands can impose such bias, yet how subtle chemical changes within these pockets reshape receptor-transducer coupling and downstream signaling remains unclear. Here, we systematically fine-tuned the intracellular allosteric pocket of neurotensin receptor 1 (NTSR1) through chemical modification of the {beta}-arrestin-biased ligand SBI-553. Minor changes to the ligand scaffold altered transducer-coupling preferences, generating distinct profiles of G-protein and {beta}-arrestin signaling. Cryo-electron microscopy structures of NTSR1-{beta}-arrestin2 complexes bound to designed allosteric probes revealed ligand-dependent remodeling of the intracellular cavity that reshapes the receptor-effector interface. Alanine scanning identified transducer-sensitive residues within and beyond the immediate ligand-contact region. In mice, SBI-553 and N065 produced distinct physiological profiles, with N065 improving survival in a lethal endotoxemia model. Finally, phosphoproteomic profiling revealed partially overlapping but distinct downstream signaling profiles among the three modulators. Together, these findings establish the intracellular allosteric pocket as a tunable determinant of transducer coupling and show that closely related modulators can generate distinct signaling and physiological profiles.",
  "abstract_shown": true,
  "affiliations": [
    "School of Medicine, Shanghai Jiao Tong University"
  ],
  "article_type": "New results",
  "arxiv": null,
  "author_total": 19,
  "authors": [
    {
      "name": "X. Shi"
    },
    {
      "name": "R. Zhu"
    },
    {
      "name": "K. Chang"
    },
    {
      "name": "P. Yu"
    },
    {
      "name": "Q. Yuan"
    },
    {
      "affs": [
        0
      ],
      "name": "Y. Zhang"
    },
    {
      "name": "X. Lu"
    },
    {
      "name": "Z. Zhou"
    },
    {
      "name": "C. Zhu"
    },
    {
      "name": "X. Lan"
    },
    {
      "name": "M. Li"
    },
    {
      "name": "R. Li"
    },
    {
      "name": "X. Qiao"
    },
    {
      "name": "W. Xie"
    },
    {
      "name": "Y. Zhuang"
    },
    {
      "name": "H. E. Xu"
    },
    {
      "name": "W. Yin"
    },
    {
      "name": "M. Zhao"
    },
    {
      "affs": [
        0
      ],
      "name": "J. Zhang"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/2hq3d7eb4kytr.bib",
  "cited_by": 0,
  "doi": "10.64898/2026.10.22.760766",
  "fulltext_url": "https://www.biorxiv.org/content/10.64898/2026.10.22.760766v1.full",
  "id": "2hq3d7eb4kytr",
  "issns": [],
  "landing_url": "https://www.biorxiv.org/content/10.64898/2026.10.22.760766v1",
  "language": null,
  "licence": "CC-BY-NC-ND",
  "licence_label": "CC BY-NC-ND",
  "licence_source": "article",
  "licence_url": "https://creativecommons.org/licenses/by-nc-nd/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "biorxiv",
      "pharmacology and toxicology"
    ],
    [
      "openalex",
      "1312|Receptor Mechanisms and Signaling"
    ]
  ],
  "openalex": "W7223973576",
  "pdf_url": "https://www.biorxiv.org/content/10.64898/2026.10.22.760766v1.full.pdf",
  "pmcid": null,
  "pmid": null,
  "published": "2026-10-22",
  "publisher": null,
  "ris": "https://research.draconitic.com/paper/2hq3d7eb4kytr.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T12:29:51Z",
      "native_id": "10.64898/2026.10.22.760766",
      "source": "biorxiv",
      "url": "https://www.biorxiv.org/content/10.64898/2026.10.22.760766v1"
    }
  ],
  "subjects": [
    {
      "field": "medicine",
      "origin": "biorxiv:pharmacology and toxicology",
      "subfield": "pharmacology-toxicology"
    }
  ],
  "title": "Fine-tuning an intracellular allosteric pocket programs GPCR signaling bias",
  "title_text": "Fine-tuning an intracellular allosteric pocket programs GPCR signaling bias",
  "type": "preprint",
  "updated_at": "2026-10-30T12:29:51Z",
  "url": "https://research.draconitic.com/paper/2hq3d7eb4kytr",
  "venue": "bioRxiv",
  "versions": []
}