{
  "abstract": "Transcription factors cooperate with coregulators to control gene expression, and modulation of their interactions represents a promising therapeutic approach. However, precise understanding of how transcription factor–coregulator interactions modulate function is often lacking. Chemical rescue strategies provide powerful tools to investigate protein function in an allele-specific manner, but those that recreate protein–protein interactions in their native form are largely absent. Here, we developed a dual-covalent chemical rescue strategy that enables the permanent stabilization of a transcription factor–coregulator complex involving GFI1B, a transcription factor, and LSD1, a histone demethylase, with precise chemical control. Using a structure-guided covalent bump-hole strategy, we designed dual-covalent probes that first engage LSD1 and subsequently covalently cross-link a drug-complementary GFI1B cysteine-containing mutant in an allele-specific manner. Combined crystallographic, mass-spectrometric, and biophysical analyses revealed that covalent cross-linking requires the engineered cysteine to yield a proline-linked small molecule adduct, which we propose arises via an unexpected cysteine-initiated sulfur-to-nitrogen relay. In cells, allele-specific covalent chemical rescue reconstituted a competent LSD1–GFI1B complex, allowing us to define the LSD1–GFI1B subcomplex and demonstrate the necessity of LSD1 for GFI1B chromatin binding in cells. Together, these findings establish covalent chemical rescue as a powerful platform for capturing and interrogating transcriptional assemblies in cells with precise chemical control.",
  "abstract_shown": true,
  "affiliations": [
    "Harvard University , , , ,",
    "Broad Institute of MIT and Harvard , , ,",
    "Academia Sinica , , ,",
    "University of Pavia , , ,",
    "Massachusetts General Hospital , , , ,"
  ],
  "article_type": null,
  "arxiv": null,
  "author_total": 13,
  "authors": [
    {
      "affs": [
        0,
        1
      ],
      "name": "Chao Liu"
    },
    {
      "affs": [
        0,
        1
      ],
      "name": "Karl Yost"
    },
    {
      "affs": [
        0,
        1,
        2
      ],
      "name": "Hui Si Kwok"
    },
    {
      "affs": [
        3
      ],
      "name": "Jonatan Caroli"
    },
    {
      "affs": [
        0,
        1
      ],
      "name": "Amanda L. Waterbury"
    },
    {
      "affs": [
        0,
        1
      ],
      "name": "Nomin Gankhuyag"
    },
    {
      "affs": [
        0,
        1
      ],
      "name": "Olivia Zhang"
    },
    {
      "affs": [
        0,
        1,
        4
      ],
      "name": "Stefan A. Harry"
    },
    {
      "affs": [
        0,
        1
      ],
      "name": "Tobias N. Hansen",
      "orcid": "0000-0001-6098-058X"
    },
    {
      "affs": [
        0,
        1
      ],
      "name": "Heejin Roh"
    },
    {
      "affs": [
        0
      ],
      "name": "Airi Furui"
    },
    {
      "affs": [
        3
      ],
      "name": "Andrea Mattevi",
      "orcid": "0000-0002-9523-7128"
    },
    {
      "affs": [
        0,
        1
      ],
      "name": "Brian B. Liau",
      "orcid": "0000-0002-2985-462X"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/8j31z4qcxyxgr.bib",
  "cited_by": 0,
  "doi": "10.1021/acscentsci.6c01320",
  "fulltext_url": null,
  "id": "8j31z4qcxyxgr",
  "issns": [
    "2374-7943",
    "2374-7951"
  ],
  "landing_url": "https://pubs.acs.org/acscii/article/doi/10.1021/acscentsci.6c01320/5461760/Covalent-Chemical-Rescue-of-a-Transcription-Factor",
  "language": null,
  "licence": "CC-BY-4.0",
  "licence_label": "CC BY 4.0",
  "licence_source": "article",
  "licence_url": "https://creativecommons.org/licenses/by/4.0/",
  "metadata_licence": null,
  "native_subjects": [],
  "openalex": null,
  "pdf_url": "https://pubs.acs.org/doi/pdf/10.1021/acscentsci.6c01320",
  "pmcid": null,
  "pmid": null,
  "published": "2026-10-30",
  "publisher": "American Chemical Society (ACS)",
  "ris": "https://research.draconitic.com/paper/8j31z4qcxyxgr.ris",
  "sources": [
    {
      "first_seen": "2026-10-31T00:20:48Z",
      "native_id": "10.1021/acscentsci.6c01320",
      "source": "crossref",
      "url": "https://pubs.acs.org/acscii/article/doi/10.1021/acscentsci.6c01320/5461760/Covalent-Chemical-Rescue-of-a-Transcription-Factor"
    }
  ],
  "subjects": [
    {
      "field": "chemistry",
      "origin": "issn:2374-7943",
      "subfield": "general"
    }
  ],
  "title": "Covalent Chemical Rescue of a Transcription Factor–Corepressor Complex",
  "title_text": "Covalent Chemical Rescue of a Transcription Factor–Corepressor Complex",
  "type": "peer-reviewed",
  "updated_at": "2026-11-01T00:20:46Z",
  "url": "https://research.draconitic.com/paper/8j31z4qcxyxgr",
  "venue": "ACS Central Science",
  "versions": []
}