Mass spectrometry (MS) is the method of choice for the characterization of proteomes. Most proteins operate in protein complexes, where their close association modulates their function. However, with standard MS analysis the information of protein-protein interactions is lost and no structural information is retained. In order to gain structural and interactome data, new cross-linking reagents are needed that freeze inter- and intramolecular interactions. Here, we report the development of a new reagent, which has several features that enable highly sensitive cross-linking MS. The reagent enables enrichment of cross-linked peptides from the majority of background peptides to facilitate efficient detection of low abundant cross-linked peptides. Due to the special cleavable properties, the reagent can be utilised for MS²- and potentially for MS³-experiments. Thus our new cross-linking reagent, in combination with high end MS, should enable sensitive analysis of interactomes, which will help researchers to obtain important insights into cellular states in health and diseases.