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Assigning functionality to cysteines by base editing of cancer dependency genes
Haoxin Li1, Tiantai Ma2, Jarrett R Remsberg3
1Department of Chemistry, Scripps Research, La Jolla, CA, USA. haoxinli@scripps.edu.
Nature Chemical Biology
|October 2, 2023
Summary
This study introduces a base-editing method to identify functional cysteines in human proteins, creating an atlas of over 13,800 cysteines. This resource helps discover new drug targets by pinpointing essential cysteines in cancer cells.
Area of Science:
- Biochemistry
- Chemical Biology
- Proteomics
Background:
- Covalent chemistry offers a way to target proteins, with chemical proteomics identifying many reactive cysteines.
- Determining the functional impact of these covalent modifications on protein activity is a significant challenge in drug discovery.
Purpose of the Study:
- To develop a base-editing strategy for assessing cysteine functionality by measuring the effect of missense mutations on cancer cell proliferation.
- To create a comprehensive atlas of cysteine functionality in cancer-relevant proteins.
Main Methods:
- Utilized a base-editing approach to systematically mutate cysteines in cancer dependency proteins.
- Quantified the impact of these mutations on cancer cell proliferation.
- Integrated findings with chemical proteomics data to identify essential, ligandable cysteines.
Main Results:
- Generated an atlas of over 13,800 cysteines across more than 1,750 cancer dependency proteins.
- Confirmed the importance of cysteines targeted by existing covalent drugs.
- Identified over 160 essential, ligandable cysteines in cancer proteins when combining base-editing and chemical proteomics data.
- Demonstrated that a targeted ligand inhibits TOE1 nuclease activity via an allosteric mechanism by binding an essential cysteine.
Conclusions:
- The developed base-editing strategy is a versatile tool for inferring cysteine functionality.
- The created atlas serves as a valuable resource for prioritizing small-molecule probes with high potential to perturb protein function.
- This work advances the discovery of targeted covalent inhibitors for cancer therapy.
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