{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,10,2]],"date-time":"2026-10-02T03:57:07Z","timestamp":1790913427813,"version":"4.1.0"},"posted":{"date-parts":[[2026,9,28]]},"group-title":"Bioengineering","reference-count":68,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,9,28]],"date-time":"2026-09-28T00:00:00Z","timestamp":1790553600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"name":"National Institutes of Health","award":["R00GM135519"],"award-info":[{"award-number":["R00GM135519"]}]},{"name":"National Institutes of Health","award":["R01CA214608"],"award-info":[{"award-number":["R01CA214608"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,9,29]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>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\u2013target pairs can be repurposed into a broadly applicable platform for protein labeling.<\/jats:p>","DOI":"10.64898\/2026.09.27.754867","type":"posted-content","created":{"date-parts":[[2026,9,28]],"date-time":"2026-09-28T21:30:18Z","timestamp":1790631018000},"source":"Crossref","is-referenced-by-count":0,"title":["Deep-learning-based design of an orthogonal self-labeling protein from K-Ras(G12C)"],"prefix":"10.64898","author":[{"given":"Jody","family":"Mou","sequence":"first","affiliation":[{"name":"Harvard and MIT Division of Health Science and Technology, Massachusetts Institute of Technology, Cambridge, MA, USA"},{"name":"Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jing Wesley","family":"Leong","sequence":"additional","affiliation":[{"name":"Broad Institute of MIT and Harvard, 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