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we present the development of a native chemical ligation handle that also functions as a masked electrophile that can be liberated during synthesis when required . 
 this handle can thus be used for the synthesis of complex activity - based probes . 
 we describe the use of this handle in the generation of linkage - specific activity - based deubiquitylating enzyme probes that contain substrate context and closely mimic the native ubiquitin isopeptide linkage . 
 we have generated activity - based probes based on all seven isopeptide - linked diubiquitin topoisomers and demonstrated their structural integrity and ability to label dubs in a linkage - specific manner .