{
  "abstract": "Self-labeling protein (SLP) tags enable versatile labeling of proteins in live cells, yet only two SLPs are commonly used, limiting multiplexing. Here, we repurposed the oncoprotein K-Ras(G12C) and its covalent inhibitors to create a third, orthogonal SLP system. We used a deep-learning-based approach to radically redesign the sequence of K-Ras(G12C) while preserving its covalent-inhibitor binding pocket. Our top design, LUCI-tag, is a 19 kDa, monomeric, thermostable SLP that rapidly and covalently reacts with commercially available K-Ras(G12C) inhibitors bearing diverse payloads. Unlike existing SLPs, LUCI-tag exhibited payload-agnostic labeling kinetics, outperforming HaloTag7 and SNAP-tag for a negatively charged payload. X-ray crystal structures of drug-bound and drug-free LUCI-tag showed the design was structurally accurate and contained a preorganized inhibitor-binding pocket that could explain its rapid labeling kinetics. Proteomics and cell-signaling experiments confirmed LUCI-tag is biologically inert. LUCI-tag enabled rapid, wash-free, live-cell imaging and simultaneous three-color multiplexed experiments with HaloTag7 and SNAP-tag. This work establishes LUCI-tag as an immediately useful orthogonal SLP and demonstrates that covalent drug-target pairs can be repurposed into a broadly applicable platform for protein labeling.",
  "abstract_shown": true,
  "affiliations": [
    "Dana-Farber Cancer Institute"
  ],
  "article_type": "New results",
  "arxiv": null,
  "author_total": 16,
  "authors": [
    {
      "name": "J. Mou"
    },
    {
      "name": "J. W. Leong"
    },
    {
      "name": "S. Gao"
    },
    {
      "name": "K. Slaw"
    },
    {
      "name": "M. McGill"
    },
    {
      "name": "K. A. Donovan"
    },
    {
      "name": "R. J. Metivier"
    },
    {
      "name": "F. L. Sendker"
    },
    {
      "name": "Q. Kong"
    },
    {
      "name": "D. Lin"
    },
    {
      "name": "A. M. Dharani"
    },
    {
      "name": "X. D. Chen"
    },
    {
      "name": "K. M. Haigis"
    },
    {
      "name": "E. S. Fischer"
    },
    {
      "name": "F. Chen"
    },
    {
      "affs": [
        0
      ],
      "name": "N. F. Polizzi"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/54ssrr8263b3v.bib",
  "cited_by": 0,
  "doi": "10.64898/2026.09.27.754867",
  "fulltext_url": "https://www.biorxiv.org/content/10.64898/2026.09.27.754867v1.full",
  "id": "54ssrr8263b3v",
  "issns": [],
  "landing_url": "https://www.biorxiv.org/content/10.64898/2026.09.27.754867v1",
  "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",
      "bioengineering"
    ],
    [
      "openalex",
      "1605|Click Chemistry and Applications"
    ]
  ],
  "openalex": "W7214650801",
  "pdf_url": "https://www.biorxiv.org/content/10.64898/2026.09.27.754867v1.full.pdf",
  "pmcid": null,
  "pmid": null,
  "published": "2026-09-27",
  "publisher": null,
  "ris": "https://research.draconitic.com/paper/54ssrr8263b3v.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T12:24:55Z",
      "native_id": "10.64898/2026.09.27.754867",
      "source": "biorxiv",
      "url": "https://www.biorxiv.org/content/10.64898/2026.09.27.754867v2"
    }
  ],
  "subjects": [
    {
      "field": "biology",
      "origin": "biorxiv:bioengineering",
      "subfield": "systems-synthetic"
    }
  ],
  "title": "Deep-learning-based design of an orthogonal self-labeling protein from K-Ras(G12C)",
  "title_text": "Deep-learning-based design of an orthogonal self-labeling protein from K-Ras(G12C)",
  "type": "preprint",
  "updated_at": "2026-10-30T12:25:04Z",
  "url": "https://research.draconitic.com/paper/54ssrr8263b3v",
  "venue": "bioRxiv",
  "versions": []
}