Cisplatin is the most widely used chemotherapeutics for cancer treatment. Cisplatin binds to DNA and impairs DNA replications and cell divisions. However, treatment by the cisplatin has numerous side-effects such as hearing loss, neuropathies, and acute renal failure. Our studies suggested that acute renal failure can be explained by interaction of cisplatin with the Na+/K+-ATPase. This membrane protein transports sodium and potassium ions and it is responsible for maintaining of electrochemical potential and sodium gradient across the plasma membrane. We used crystallographic analysis to reveal cisplatin binding sites on the Na+/K+-ATPase. Despite a moderate resolution of crystals (7.4 Å and 7.9 Å), we found seven cisplatin binding sites on the protein. Our results suggested that there are two possible inhibitory mechanisms for cisplatin. First, binding to Met151 can block the N-terminal pathway for transported ions, and second, binding to Met171 can hinder the interaction of cytoplasmic domains during the catalytic cycle.
Acknowledgement
This work was supported by grant IGA_PrF_2014_029 from Palacky University in Olomouc and by grant CZ.1.07/2.3.00/20.0057 from Czech Ministry of Education, Youth ans Sports.