{"title":"Selective photo crosslinking to methylarginine readers by sulfonium peptides.","authors":"Ting Luo, Feng Feng, Kun Zou, Yumo Zhao, Yingxiao Gao, Mingxuan Wu","doi":"10.1016/j.bmc.2024.118015","DOIUrl":null,"url":null,"abstract":"<p><p>Arginine methylation is an important posttranslational modification that regulates epigenetics and pre-mRNA splicing. Similar to lysine methylation, reader proteins that bind site-specific modified proteins are key mediators for arginine methylation functions. Some arginine methylation has been shown significant functions from phenotype, but the molecular mechanisms remain elusive, probably due to lack of identification of the readers. Current methods rely on methylarginine peptide tools for pull-down or binding assays, but affinities to readers are usually tens to hundreds micromolar. As a consequence, development of chemical probes that crosslink specific readers is much in demand. We recently reported a methyllysine reader-selective crosslinking strategy by sulfonium peptides. NleS<sup>+</sup>me2 (norleucine-ε-dimethylsulfonium) imitate dimethyllysine and crosslink tryptophan or tyrosine inside binding pocket of readers. Arginine methylation readers contain aromatic cages for methylarginine binding, that is the similar binding mechanism for methyllysine. Therefore, we developed sulfonium probes that mimic methylarginine and crosslink tryptophan or tyrosine inside reader binding pockets. Because the single electron transfer from aromatic residue to sulfonium is binding-dependent, the conjugation showed high selectivity. Therefore, such sulfonium probes could be applied broadly for methylarginine readers investigations.</p>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":"118 ","pages":"118015"},"PeriodicalIF":3.3000,"publicationDate":"2024-11-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Bioorganic & Medicinal Chemistry","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1016/j.bmc.2024.118015","RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"BIOCHEMISTRY & MOLECULAR BIOLOGY","Score":null,"Total":0}
引用次数: 0
Abstract
Arginine methylation is an important posttranslational modification that regulates epigenetics and pre-mRNA splicing. Similar to lysine methylation, reader proteins that bind site-specific modified proteins are key mediators for arginine methylation functions. Some arginine methylation has been shown significant functions from phenotype, but the molecular mechanisms remain elusive, probably due to lack of identification of the readers. Current methods rely on methylarginine peptide tools for pull-down or binding assays, but affinities to readers are usually tens to hundreds micromolar. As a consequence, development of chemical probes that crosslink specific readers is much in demand. We recently reported a methyllysine reader-selective crosslinking strategy by sulfonium peptides. NleS+me2 (norleucine-ε-dimethylsulfonium) imitate dimethyllysine and crosslink tryptophan or tyrosine inside binding pocket of readers. Arginine methylation readers contain aromatic cages for methylarginine binding, that is the similar binding mechanism for methyllysine. Therefore, we developed sulfonium probes that mimic methylarginine and crosslink tryptophan or tyrosine inside reader binding pockets. Because the single electron transfer from aromatic residue to sulfonium is binding-dependent, the conjugation showed high selectivity. Therefore, such sulfonium probes could be applied broadly for methylarginine readers investigations.
期刊介绍:
Bioorganic & Medicinal Chemistry provides an international forum for the publication of full original research papers and critical reviews on molecular interactions in key biological targets such as receptors, channels, enzymes, nucleotides, lipids and saccharides.
The aim of the journal is to promote a better understanding at the molecular level of life processes, and living organisms, as well as the interaction of these with chemical agents. A special feature will be that colour illustrations will be reproduced at no charge to the author, provided that the Editor agrees that colour is essential to the information content of the illustration in question.