Updated publication reference for PubMed record(s): 29199018. While modern structural biology technologies have greatly expanded the size and type of protein complexes that can now be studied, the ability to derive large-scale structural information on proteins and complexes as they exist within tissues is practically non-existent. Many protein properties and their involvement in disease pathways are not replicated in cell culture and some complexes are not amenable to purification. Thus, the lack of tissue-level structural information limits molecular-level insight on diseases such as heart failure. Here we demonstrate the application of XL-MS to identify protein structural features and interactions in tissue samples, providing the first systems structural biology insight on protein complexes as they exist in the mouse heart.