The DIPP1 family binds IP8 in catalytically-productive twist-boat and chair conformations and associates in a ligand-dependent manner

Journal article

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.

Authors: Casas-Florez, D; Whitfield, H; Pérez-Cañadillas, JM; Monterroso, B; Riley, AM

• Publication status: In press
• Peer review status: Peer reviewed
• Publisher: Elsevier
• Journal: International Journal of Biological Macromolecules
• Article number: 152715
• Publication date: 2026-05-26
• Acceptance date: 2026-05-24
• DOI: 10.1016/j.ijbiomac.2026.152715
• EISSN: 1879-0003
• ISSN: 0141-8130
• Language: English
• Keywords: twist-boat; IP8; DIPP1; inositol polyphosphate; inositol pyrophosphate; nudix hydrolase