Selective Protein Degradation through Tetrazine Ligation of Genetically Incorporated Unnatural Amino Acids
Abstract: Small molecule‐responsive tags for targeted protein degradation are valuable tools for fundamental research and drug target validation. Here, we show that genetically incorporated unnatural amino acids bearing a strained alkene or alkyne functionality can act as a minimalist tag for targeted protein degradation. Specifically, we observed the degradation of strained alkene‐ or alkyne‐containing kinases and E2 ubiquitin‐conjugating enzymes upon treatment with hydrophobic tetrazine conjugates. The extent of the induced protein degradation depends on the identity of the target protein, unnatural amino acid, and tetrazine conjugate, as well as the site of the unnatural amino acid in the target protein. Mechanistic studies revealed proteins undergo proteasomal degradation after tetrazine tethering, and the identity of tetrazine conjugates influences the dependence of ubiquitination on protein degradation. This work provides an alternative approach for targeted protein degradation and mechanistic insight, facilitating the future development of more effective targeted protein degradation strategies.
- Location
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Deutsche Nationalbibliothek Frankfurt am Main
- Extent
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Online-Ressource
- Language
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Englisch
- Bibliographic citation
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Selective Protein Degradation through Tetrazine Ligation of Genetically Incorporated Unnatural Amino Acids ; day:26 ; month:10 ; year:2024 ; extent:10
Chemistry ; (26.10.2024) (gesamt 10)
- Creator
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Chen, Jinghao
Dai, Gaocan
Duan, Shixiang
Huang, Yang
Wu, Yi‐Lin
Xie, Zhiyong
Tsai, Yu‐Hsuan
- DOI
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10.1002/asia.202400824
- URN
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urn:nbn:de:101:1-2410271304172.588043788496
- Rights
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Open Access; Der Zugriff auf das Objekt ist unbeschränkt möglich.
- Last update
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15.07.2025, 12:00 AM CEST
Data provider
Deutsche Nationalbibliothek. If you have any questions about the object, please contact the data provider.
Associated
- Chen, Jinghao
- Dai, Gaocan
- Duan, Shixiang
- Huang, Yang
- Wu, Yi‐Lin
- Xie, Zhiyong
- Tsai, Yu‐Hsuan
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