The human enzyme p97, a hexameric AAA+ protein, plays a crucial role in regulating various cellular pathways by unfolding protein substrates in an ATP-dependent manner. This study investigates the molecular mechanisms underlying p97's ATP processing at the atomic level using a multidisciplinary approach, including cryo-EM, NMR spectroscopy, and molecular dynamics (MD) simulations. The research reveals that p97 adopts a metastable ADP-Pi state, poised between ATP hydrolysis and product release, where the active site is fine-tuned to trap and release the cleaved phosphate. The N-terminal domain (NTD) undergoes significant conformational changes, transitioning from an 'up' to a 'down' position, which is linked to the nucleotide state. The study also identifies key residues and pathways that coordinate the action of subunits and couple ATP hydrolysis with allosteric conformational changes. The findings provide insights into the sophisticated spatial and temporal orchestration of ATP handling by a prototype AAA+ protein, highlighting the importance of the sensor loop in inter-subunit communication and the role of specific residues in ATPase activity.The human enzyme p97, a hexameric AAA+ protein, plays a crucial role in regulating various cellular pathways by unfolding protein substrates in an ATP-dependent manner. This study investigates the molecular mechanisms underlying p97's ATP processing at the atomic level using a multidisciplinary approach, including cryo-EM, NMR spectroscopy, and molecular dynamics (MD) simulations. The research reveals that p97 adopts a metastable ADP-Pi state, poised between ATP hydrolysis and product release, where the active site is fine-tuned to trap and release the cleaved phosphate. The N-terminal domain (NTD) undergoes significant conformational changes, transitioning from an 'up' to a 'down' position, which is linked to the nucleotide state. The study also identifies key residues and pathways that coordinate the action of subunits and couple ATP hydrolysis with allosteric conformational changes. The findings provide insights into the sophisticated spatial and temporal orchestration of ATP handling by a prototype AAA+ protein, highlighting the importance of the sensor loop in inter-subunit communication and the role of specific residues in ATPase activity.