Covalent probes serve as valuable tools for global investigation of protein function and ligand binding capacity. Despite efforts to expand coverage of residues available for chemical proteomics (e.g., cysteine and lysine), a large fraction of the proteome remains inaccessible with current activity-based probes. Here, we introduce sulfur-triazole exchange (SuTEx) chemistry as a tunable platform for developing covalent probes with broad applications for chemical proteomics. We show modifications to the triazole leaving group can furnish sulfonyl probes with ~5-fold enhanced chemoselectivity for tyrosines over other nucleophilic amino acids to investigate more than 10,000 tyrosine sites in lysates and live cells. We discover that tyrosines with enhanced nucleophilicity are enriched in enzymatic, protein-protein interaction and nucleotide recognition domains. We apply SuTEx as a chemical phosphoproteomics strategy to monitor activation of phosphotyrosine sites. Collectively, we describe SuTEx as a biocompatible chemistry for chemical biology investigations of the human proteome.

中文翻译：

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使用硫代三唑交换化学方法对功能性酪氨酸进行全局靶向。

共价探针是蛋白质功能和配体结合能力的全面研究的有价值的工具。尽管努力扩大可用于化学蛋白质组学的残基（例如半胱氨酸和赖氨酸）的覆盖范围，但是目前的基于活性的探针仍无法接近大部分蛋白质组。在这里，我们介绍了硫三唑交换（SuTEx）化学方法作为开发共价探针的可调平台，该共价探针在化学蛋白质组学中具有广泛的应用。我们显示出对三唑离去基团的修饰可以使磺酰探针对酪氨酸的化学选择性比其他亲核氨基酸高约5倍，以研究裂解液和活细胞中超过10,000个酪氨酸的位点。我们发现，具有增强亲核性的酪氨酸富含酶促，蛋白质-蛋白质相互作用和核苷酸识别域。我们将SuTEx作为一种化学磷酸化蛋白质组学策略来监测磷酸酪氨酸位点的激活。总的来说，我们将SuTEx描述为一种用于人类蛋白质组化学生物学研究的生物相容性化学物质。