The homohexameric AAA+ ATPase p97 plays an important role in protein homeostasis in the cell. Missense mutations in p97 gene cause 50% of multisystem proteionopathy (MSP) and it can affect the muscles, bone and brain One of such most clinically relevant mutations is R155P which is located at N-D1 interface. This variant has been found to form hexamer in the same way as its wild type counterpart and has an increased ATPase activity. However, the subtle effect of this mutation on the structure-function behaviour of p97 is not deciphered yet. Herein, with the aid of state of the art high resolution single particle cryo-EM technique, we solved the structure of p97R155P in different nucleotide loaded states (ADP and ATP analogue, ATPγS) at near atomic resolutions. The structural information gained thereof not only enabled us to address the effect of the disease-causing mutation but also uncovers the molecular basis of nucleotide dependent conformational changes, driving p97 function. The novel structural disposition of p97R155P in different nucleotide bound states can further be envisaged to design structure-based drugs for treatment of cancer (with increased expression of p97) and neurodegenerative diseases.