De novo design of Ras isoform selective binders
Jason Z Zhang1, Xinting Li2, Alexa Rane Batingana3
1Department of Biochemistry, University of Washington, Seattle, WA 98195, USA; Institute for Protein Design, University of Washington, Seattle, WA 98195, USA; Howard Hughes Medical Institute, University of Washington, Seattle, WA 98195, USA; Department of Bioengineering, University of California, Los Angeles, Los Angeles, CA 90095, USA; Biological Physics, Structure and Design Graduate Program, University of Washington, Seattle, WA 98195, USA.
Researchers developed novel Ras isoform-specific binders (RIBs) using deep learning to target cancer-associated Ras proteins. These RIBs demonstrate high specificity, inhibiting Ras activity and offering potential for cancer therapy and understanding resistance mechanisms.
Area of Science:
- Oncology
- Molecular Biology
- Bioinformatics
Background:
- RAS proto-oncogenes encode four major isoforms implicated in cancer.
- Limited availability of isoform-specific binding reagents hinders research due to conserved sequences, except for C-terminal differences.
Purpose of the Study:
- To design novel, de novo Ras isoform-specific binders (RIBs) targeting the Ras C-terminus.
- To overcome the challenge of limited isoform specificity in existing reagents.
- To explore the utility of RIBs in understanding Ras biology and cancer.
Main Methods:
- Deep learning-based methods were employed to design RIBs targeting the Ras C-terminus.
- In vitro and cellular assays were used to validate RIB binding and specificity.
- RIBs were used to investigate Ras isoform roles in RasG12C inhibitor resistance.
Main Results:
- De novo designed RIBs demonstrated high specificity for target Ras isoforms.
- RIBs effectively bind both in vitro and within cells.
- RIBs disrupt Ras membrane localization and inhibit Ras activity.
- RIBs facilitated the dissection of distinct Ras isoform roles in RasG12C inhibitor resistance.
Conclusions:
- Deep learning enables the creation of highly specific Ras isoform binders.
- RIBs are valuable tools for dissecting Ras isoform functions in biological processes and disease.
- RIBs show promise for therapeutic applications in cancer treatment.
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