{"title":"通过与基因结合的非天然氨基酸的四嗪连接选择性降解蛋白质。","authors":"Jinghao Chen, Gaocan Dai, Shixiang Duan, Yang Huang, Yi-Lin Wu, Zhiyong Xie, Yu-Hsuan Tsai","doi":"10.1002/asia.202400824","DOIUrl":null,"url":null,"abstract":"<p><p>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.</p>","PeriodicalId":145,"journal":{"name":"Chemistry - An Asian Journal","volume":null,"pages":null},"PeriodicalIF":3.5000,"publicationDate":"2024-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Selective Protein Degradation through Tetrazine Ligation of Genetically Incorporated Unnatural Amino Acids.\",\"authors\":\"Jinghao Chen, Gaocan Dai, Shixiang Duan, Yang Huang, Yi-Lin Wu, Zhiyong Xie, Yu-Hsuan Tsai\",\"doi\":\"10.1002/asia.202400824\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><p>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.</p>\",\"PeriodicalId\":145,\"journal\":{\"name\":\"Chemistry - An Asian Journal\",\"volume\":null,\"pages\":null},\"PeriodicalIF\":3.5000,\"publicationDate\":\"2024-09-02\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Chemistry - An Asian Journal\",\"FirstCategoryId\":\"1\",\"ListUrlMain\":\"https://doi.org/10.1002/asia.202400824\",\"RegionNum\":3,\"RegionCategory\":\"化学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q2\",\"JCRName\":\"CHEMISTRY, MULTIDISCIPLINARY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Chemistry - An Asian Journal","FirstCategoryId":"1","ListUrlMain":"https://doi.org/10.1002/asia.202400824","RegionNum":3,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"CHEMISTRY, MULTIDISCIPLINARY","Score":null,"Total":0}
Selective Protein Degradation through Tetrazine Ligation of Genetically Incorporated Unnatural Amino Acids.
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.
期刊介绍:
Chemistry—An Asian Journal is an international high-impact journal for chemistry in its broadest sense. The journal covers all aspects of chemistry from biochemistry through organic and inorganic chemistry to physical chemistry, including interdisciplinary topics.
Chemistry—An Asian Journal publishes Full Papers, Communications, and Focus Reviews.
A professional editorial team headed by Dr. Theresa Kueckmann and an Editorial Board (headed by Professor Susumu Kitagawa) ensure the highest quality of the peer-review process, the contents and the production of the journal.
Chemistry—An Asian Journal is published on behalf of the Asian Chemical Editorial Society (ACES), an association of numerous Asian chemical societies, and supported by the Gesellschaft Deutscher Chemiker (GDCh, German Chemical Society), ChemPubSoc Europe, and the Federation of Asian Chemical Societies (FACS).