Diphosphoinositol Polyphosphate Phosphohydrolase 1 (DIPP1) is a Nudix hydrolase involved in inositol pyrophosphate (PP-InsP) metabolism, critical for cellular signaling, energy homeostasis, and stress responses. We report crystallographic and computational studies that reveal 1,5-bis-diphosphoinositol tetrakisphosphate (IP8) binds to DIPP1 in two catalytically-productive inositol ring conformations. IP8 hydrolysis at the 1-position requires a twist-boat conformation, whereas at the 5-position a canonical chair conformation is adopted. Additionally, structural and biophysical characterization shows that the DIPP1 family undergoes ligand-sensitive changes in the association state that might be further modulated by salt concentration and/or phosphate ions. Taken together, these results advance our understanding of DIPP1 in the dynamic regulation of inositol pyrophosphate signaling networks. They provide a detailed view of DIPP1 substrate recognition and suggest oligomerization as a novel regulatory mechanism, with broader implications for phosphate sensing and functional protein-protein interactions.