De novo design of Ras isoform selective binders
Open accessPublished version of a preprint
Abstract
Abstract The proto-oncogene Ras which governs diverse intracellular pathways has four major isoforms (KRAS4A, KRAS4B, HRAS, and NRAS) with substantial sequence homology and similar in vitro biochemistry. There is considerable interest in investigating the roles of these independently as their association with different cancers vary, but there are few Ras isoform-specific binding reagents as the only significant sequence differences are in their disordered and highly charged C-termini which have been difficult to elicit antibodies against. To overcome this limitation, we use deep learning-based methods to de novo design Ras isoform-specific binders (RIBs) for all major Ras isoforms that specifically target the Ras C-terminus. The RIBs bind to their target Ras isoforms both in vitro and in cells with remarkable specificity, disrupting their membrane localization and inhibiting Ras activity, and should contribute to dissecting the distinct roles of Ras isoforms in biology and disease.
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Cites
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Self-citationDe novo design of protein structure and function with RFdiffusion
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“While KRAS4A and KRAS4B Ras-less MEFs displayed transient activation of Ras with Ras signaling returning to baseline or lower levels, NRAS and HRAS Ras-less MEFs showed transient Ras activation where Ras activity persists 10 min after EGF stimulation 30 (Figure 4B).”
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- Authors
- Zhang, J. Z., Li, X., Batingana, A. R., Liu, C., Jiang, H., Shannon, K., Huang, B. J., Wu, K., & Baker, D.
- Affiliations
- Howard Hughes Medical Institute (US)
- University of Washington (US)
- University of California, San Francisco (US)
- Corresponding author
- Zhang, Jason Z.
- Wu, Kejia
- Baker, David
- Venue
- Cell Chemical Biology
- Publisher
- Elsevier BV
- Published
- 2026-03
- Volume
- 33
- Issue
- 3
- Pages
- 396-408.e7
- ISSN
- 2451-9448 (ISSN-L)
- 2451-9456
- PMC
- PMC11838417
- OpenAlex
- W7135028729
- Cited by
- 12
- References
- 9
- Citations by year
- 2026: 6 · 2025: 6
- FWCI
- 12.40
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Cell chemical biology (publishedVersion, cc-by)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed Central (submittedVersion, cc-by-nc-nd)
- Funders
- Helen Hay Whitney Foundation
- National Institutes of Health National Cancer Institute
- National Institutes of Health
- Howard Hughes Medical Institute
- Croucher Foundation
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Physical Sciences › Computer Science › Computational Theory and Mathematics › Computational Drug Discovery Methods
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Degradation and Inhibitors
- Keywords
- Ras isoforms, de novo design, RAS inhibitors, inhibitor resistance, therapeutic applications
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