This dataset assesses structural changes occurring in human, heme-bound HRI upon association with S-DELE1. To this end, human HRI and S-DELE1 were expressed EIF2alpha phosphorylation-resistent cells supplemented with hemin. HRI was affinity purified, crosslinked with DSS, and structural changes in HRI were assessed by MS. The data set identifies S-DELE1 induced structural changes in the C-terminal region and the kinase insert of HRI, as well as domains of HRI that are in structural proximity to S-DELE1.