Cross-linking mass spectrometry (XL-MS) has made significant progress in understanding the structure of protein and elucidating architectures of larger protein complexes. Current XL-MS applications are limited to targeting lysine, glutamic acid, aspartic acid, and cysteine residues. There remains a need for the development of novel cross-linkers enabling selective targeting of other amino acid residues in proteins. Here, a novel simple crosslinker, namely, [4,4′-(disulfanediylbis(ethane-2,1-diyl)) bis(1,2,4triazolidine-3,5-dione)] (DBB), has been designed, synthesized, and characterized. This cross-linker can react selectively with tyrosine residues in protein through the electrochemical click reaction. The DBB cross-links produced the characteristic peptides before and after electrochemical reduction, thus permitting the simplified data analysis and accurate identification for the crosslinked products. This is the first time a cross-linker is developed for targeting tyrosine residues on protein without using photoirradiation or a metal catalyst. This strategy might potentially be used as a complementary tool for XL-MS to probe protein 3D structures, protein complexes, and protein−protein interaction.

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