{"title":"锍和色氨酸之间的单电子转移实现了甲基赖氨酸阅读器蛋白质的位点选择性光交联","authors":"Feng Feng, Yingxiao Gao, Qun Zhao, Ting Luo, Qingyun Yang, Nan Zhao, Yihang Xiao, Yusong Han, Jinheng Pan, Shan Feng, Lihua Zhang, Mingxuan Wu","doi":"10.1038/s41557-024-01577-y","DOIUrl":null,"url":null,"abstract":"The identification of readers, an important class of proteins that recognize modified residues at specific sites, is essential to uncover the biological roles of post-translational modifications. Photoreactive crosslinkers are powerful tools for investigating readers. However, existing methods usually employ synthetically challenging photoreactive warheads, and their high-energy intermediates generated upon irradiation, such as nitrene and carbene, may cause substantial non-specific crosslinking. Here we report dimethylsulfonium as a methyllysine mimic that binds to specific readers and subsequently crosslinks to a conserved tryptophan inside the binding pocket through single-electron transfer under ultraviolet irradiation. The crosslinking relies on a protein-templated σ–π electron donor–acceptor interaction between sulfonium and indole, ensuring excellent site selectivity for tryptophan in the active site and orthogonality to other methyllysine readers. This method could escalate the discovery of methyllysine readers from complex cell samples. Furthermore, this photo crosslinking strategy could be extended to develop other types of microenvironment-dependent conjugations to site-specific tryptophan. Tryptophan plays important biological roles in aromatic cages, such as methyllysine recognition, but the development of site-selective crosslinking to tryptophan is challenging. Now sulfonium can be used as a methyllysine mimic that binds to reader proteins and crosslinks tryptophan inside a pocket through single-electron transfer. This strategy enables the identification of methyllysine readers from the proteome.","PeriodicalId":18909,"journal":{"name":"Nature chemistry","volume":null,"pages":null},"PeriodicalIF":19.2000,"publicationDate":"2024-07-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Single-electron transfer between sulfonium and tryptophan enables site-selective photo crosslinking of methyllysine reader proteins\",\"authors\":\"Feng Feng, Yingxiao Gao, Qun Zhao, Ting Luo, Qingyun Yang, Nan Zhao, Yihang Xiao, Yusong Han, Jinheng Pan, Shan Feng, Lihua Zhang, Mingxuan Wu\",\"doi\":\"10.1038/s41557-024-01577-y\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"The identification of readers, an important class of proteins that recognize modified residues at specific sites, is essential to uncover the biological roles of post-translational modifications. Photoreactive crosslinkers are powerful tools for investigating readers. However, existing methods usually employ synthetically challenging photoreactive warheads, and their high-energy intermediates generated upon irradiation, such as nitrene and carbene, may cause substantial non-specific crosslinking. Here we report dimethylsulfonium as a methyllysine mimic that binds to specific readers and subsequently crosslinks to a conserved tryptophan inside the binding pocket through single-electron transfer under ultraviolet irradiation. The crosslinking relies on a protein-templated σ–π electron donor–acceptor interaction between sulfonium and indole, ensuring excellent site selectivity for tryptophan in the active site and orthogonality to other methyllysine readers. This method could escalate the discovery of methyllysine readers from complex cell samples. Furthermore, this photo crosslinking strategy could be extended to develop other types of microenvironment-dependent conjugations to site-specific tryptophan. Tryptophan plays important biological roles in aromatic cages, such as methyllysine recognition, but the development of site-selective crosslinking to tryptophan is challenging. Now sulfonium can be used as a methyllysine mimic that binds to reader proteins and crosslinks tryptophan inside a pocket through single-electron transfer. This strategy enables the identification of methyllysine readers from the proteome.\",\"PeriodicalId\":18909,\"journal\":{\"name\":\"Nature chemistry\",\"volume\":null,\"pages\":null},\"PeriodicalIF\":19.2000,\"publicationDate\":\"2024-07-30\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Nature chemistry\",\"FirstCategoryId\":\"92\",\"ListUrlMain\":\"https://www.nature.com/articles/s41557-024-01577-y\",\"RegionNum\":1,\"RegionCategory\":\"化学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"CHEMISTRY, MULTIDISCIPLINARY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Nature chemistry","FirstCategoryId":"92","ListUrlMain":"https://www.nature.com/articles/s41557-024-01577-y","RegionNum":1,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"CHEMISTRY, MULTIDISCIPLINARY","Score":null,"Total":0}
Single-electron transfer between sulfonium and tryptophan enables site-selective photo crosslinking of methyllysine reader proteins
The identification of readers, an important class of proteins that recognize modified residues at specific sites, is essential to uncover the biological roles of post-translational modifications. Photoreactive crosslinkers are powerful tools for investigating readers. However, existing methods usually employ synthetically challenging photoreactive warheads, and their high-energy intermediates generated upon irradiation, such as nitrene and carbene, may cause substantial non-specific crosslinking. Here we report dimethylsulfonium as a methyllysine mimic that binds to specific readers and subsequently crosslinks to a conserved tryptophan inside the binding pocket through single-electron transfer under ultraviolet irradiation. The crosslinking relies on a protein-templated σ–π electron donor–acceptor interaction between sulfonium and indole, ensuring excellent site selectivity for tryptophan in the active site and orthogonality to other methyllysine readers. This method could escalate the discovery of methyllysine readers from complex cell samples. Furthermore, this photo crosslinking strategy could be extended to develop other types of microenvironment-dependent conjugations to site-specific tryptophan. Tryptophan plays important biological roles in aromatic cages, such as methyllysine recognition, but the development of site-selective crosslinking to tryptophan is challenging. Now sulfonium can be used as a methyllysine mimic that binds to reader proteins and crosslinks tryptophan inside a pocket through single-electron transfer. This strategy enables the identification of methyllysine readers from the proteome.
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