{
  "abstract": "RXFP1 is an unusual G protein-coupled receptor (GPCR) that mediates physiological adaptations to pregnancy and is a therapeutic target due to its benefits in treatment of fibrosis and heart failure. Protein and small-molecule agonists are currently in mid-stage clinical trials. Here, we present three cryo-electron microscopy structures of RXFP1: ligand-free, bound to the native agonist relaxin-2, and bound to the small-molecule drug candidate AZD5462. These structures show that relaxin-2 engages the receptor's ectodomain while AZD5462 binds within transmembrane domain. Together with hydrogen-deuterium exchange mass spectrometry, we show that relaxin-2 induces conformational reorganization of the linker domain into a helical secondary structure. In contrast, AZD5462 stabilizes a unique active conformation capable of inducing β-arrestin recruitment. Both mechanisms are distinctive from the \"push-pull\" mechanism of glycoprotein hormone receptors. Altogether, our findings define divergent activation mechanisms for protein and small-molecule agonists of RXFP1 and provide structural framework for next-generation drug discovery targeting relaxin receptors and their relatives.",
  "abstract_shown": true,
  "affiliations": [],
  "article_type": null,
  "arxiv": null,
  "author_total": 12,
  "authors": [
    {
      "name": "James Osei-Owusu"
    },
    {
      "name": "Tristan Girbau"
    },
    {
      "name": "Xunan Wang"
    },
    {
      "name": "Jeffrey S Smith"
    },
    {
      "name": "Pengxiang Shen"
    },
    {
      "name": "Sarah C Erlandson"
    },
    {
      "name": "Amanda K Williamson"
    },
    {
      "name": "Xiaojing Cong"
    },
    {
      "name": "Mark W Grinstaff"
    },
    {
      "name": "Daniel E Kahne"
    },
    {
      "name": "Cherine Bechara"
    },
    {
      "name": "Andrew C Kruse"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/b78vgb9stb5rx.bib",
  "cited_by": 0,
  "doi": "10.64898/2026.06.10.731386",
  "fulltext_url": null,
  "id": "b78vgb9stb5rx",
  "issns": [],
  "landing_url": "https://hal.science/hal-05757595v1",
  "language": "en",
  "licence": "CC-BY-NC-ND-4.0",
  "licence_label": "CC BY-NC-ND 4.0",
  "licence_source": "article",
  "licence_url": "https://creativecommons.org/licenses/by-nc-nd/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "hal",
      "0.sdv"
    ],
    [
      "hal",
      "1.sdv.bbm"
    ],
    [
      "hal",
      "1.sdv.bc"
    ],
    [
      "hal",
      "2.sdv.bbm.bs"
    ],
    [
      "openalex",
      "1312|Receptor Mechanisms and Signaling"
    ]
  ],
  "openalex": "W7164516742",
  "pdf_url": "https://hal.science/hal-05757595/document",
  "pmcid": null,
  "pmid": "42327029",
  "published": "2026-06-11",
  "publisher": null,
  "ris": "https://research.draconitic.com/paper/b78vgb9stb5rx.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T12:17:37Z",
      "native_id": "hal-05757595",
      "source": "hal",
      "url": "https://hal.science/hal-05757595v1"
    }
  ],
  "subjects": [
    {
      "field": "biochemistry",
      "origin": "hal:2.sdv.bbm.bs",
      "subfield": "structural-biology"
    },
    {
      "field": "biology",
      "origin": "hal:1.sdv.bc",
      "subfield": "cell-biology"
    }
  ],
  "title": "Divergent activation of the RXFP1 relaxin receptor by protein and small molecule agonists",
  "title_text": "Divergent activation of the RXFP1 relaxin receptor by protein and small molecule agonists",
  "type": "preprint",
  "updated_at": "2026-10-30T12:17:37Z",
  "url": "https://research.draconitic.com/paper/b78vgb9stb5rx",
  "venue": "HAL",
  "versions": []
}