{
  "abstract": "Proteolysis-targeting chimeras (PROTACs) and molecular glue degraders (MGDs) target proteins for degradation by co-opting an E3 ligase. While heterotrivalent PROTACs that can recruit multiple E3 ligases have been described, all MGDs reported to date depend on a single E3. Using orthogonal genetic screening, biophysical and structural analyses, we show that a monovalent MGD can recruit CUL4 DCAF16 and CRL1 FBXO22 in parallel to degrade SMARCA2/4. Deep mutational scanning identifies C173 in DCAF16 as essential for degrader activity and intact protein mass spectrometry confirms covalent modification at this site. Elucidating the ternary complex structure reveals a unique binding mode and a distinct interface of neointeractions that underlie degrader specificity. We demonstrate that ligase dependency is chemically and genetically tunable. Minimal compound modifications shift preference from DCAF16 to FBXO22, while a single substitution boosts degrader dependency on DCAF16. These results establish a framework for designing tunable dual E3 ligase degraders to mitigate potential resistance mechanisms.",
  "abstract_shown": true,
  "affiliations": [
    "Centre for Targeted Protein Degradation, School of Life Sciences, University of Dundee, Dundee, UK",
    "AITHYRA Research Institute for Biomedical Artificial Intelligence of the Austrian Academy of Sciences, Vienna, Austria",
    "CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria",
    "Centre for Targeted Protein Degradation, School of Life Sciences, University of Dundee, Dundee, UK. a.ciulli@dundee.ac.uk",
    "AITHYRA Research Institute for Biomedical Artificial Intelligence of the Austrian Academy of Sciences, Vienna, Austria. gwinter@aithyra.at",
    "CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria. gwinter@aithyra.at"
  ],
  "article_type": null,
  "arxiv": null,
  "author_total": 15,
  "authors": [
    {
      "affs": [
        0
      ],
      "name": "Valentina A. Spiteri",
      "orcid": "0000-0002-5002-4989"
    },
    {
      "affs": [
        1,
        2
      ],
      "name": "Dmitri Segal",
      "orcid": "0000-0003-0880-4794"
    },
    {
      "affs": [
        0
      ],
      "name": "Alejandro Correa-Sáez",
      "orcid": "0000-0001-5240-4865"
    },
    {
      "affs": [
        0
      ],
      "name": "Kentaro Iso",
      "orcid": "0000-0001-5417-3642"
    },
    {
      "affs": [
        0
      ],
      "name": "Ryan Casement",
      "orcid": "0000-0001-8075-0757"
    },
    {
      "affs": [
        1,
        2
      ],
      "name": "Miquel Muñoz i Ordoño",
      "orcid": "0009-0003-4391-6393"
    },
    {
      "affs": [
        0
      ],
      "name": "Mark A. Nakasone",
      "orcid": "0000-0002-1362-191X"
    },
    {
      "affs": [
        0
      ],
      "name": "Gajanan J. Sathe",
      "orcid": "0000-0002-6239-5365"
    },
    {
      "affs": [
        1,
        2
      ],
      "name": "Caroline Schätz",
      "orcid": "0000-0002-8391-8778"
    },
    {
      "affs": [
        0
      ],
      "name": "Hannah E. Peters"
    },
    {
      "affs": [
        0
      ],
      "name": "Mark Dorward",
      "orcid": "0000-0001-5765-0926"
    },
    {
      "affs": [
        1,
        2
      ],
      "name": "Lisa Kainacher"
    },
    {
      "affs": [
        0
      ],
      "name": "Angus D. Cowan",
      "orcid": "0000-0002-9702-7319"
    },
    {
      "affs": [
        3
      ],
      "name": "Alessio Ciulli",
      "orcid": "0000-0002-8654-1670"
    },
    {
      "affs": [
        4,
        5
      ],
      "name": "Georg E. Winter",
      "orcid": "0000-0001-6606-1437"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/1frn5jsrbbwha.bib",
  "cited_by": 14,
  "doi": "10.1038/s41589-026-02224-y",
  "fulltext_url": null,
  "id": "1frn5jsrbbwha",
  "issns": [
    "1552-4450",
    "1552-4469"
  ],
  "landing_url": "https://doi.org/10.1038/s41589-026-02224-y",
  "language": "en",
  "licence": "CC-BY",
  "licence_label": "CC BY",
  "licence_source": "journal",
  "licence_url": "https://creativecommons.org/licenses/by/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "openalex",
      "1312|Protein Degradation and Inhibitors"
    ]
  ],
  "openalex": "W7160896843",
  "pdf_url": null,
  "pmcid": "PMC13612222",
  "pmid": "42120501",
  "published": "2026-05-12",
  "publisher": "Nature Portfolio",
  "ris": "https://research.draconitic.com/paper/1frn5jsrbbwha.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T13:26:48Z",
      "native_id": "W7160896843",
      "source": "openalex",
      "url": "https://doi.org/10.1038/s41589-026-02224-y"
    }
  ],
  "subjects": [
    {
      "field": "biochemistry",
      "origin": "openalex:1312|Protein Degradation and Inhibitors",
      "subfield": "molecular-biology"
    }
  ],
  "title": "Dual E3 ligase recruitment by monovalent degraders for tunable SMARCA 2/4 degradation",
  "title_text": "Dual E3 ligase recruitment by monovalent degraders for tunable SMARCA 2/4 degradation",
  "type": "peer-reviewed",
  "updated_at": "2026-11-06T13:20:28Z",
  "url": "https://research.draconitic.com/paper/1frn5jsrbbwha",
  "venue": "Nature Chemical Biology",
  "versions": []
}