Cisplatin is the most widely used chemotherapeutics for cancer treatment, however, its administration is connected to inevitable adverse effects. Previous studies suggested that cisplatin is able to inhibit Na(+)/K(+)-ATPase (NKA), the enzyme responsible for maintaining electrochemical potential and sodium gradient across the plasma membrane. Here we report a crystallographic analysis of cisplatin bound to NKA in the ouabain bound E2P form. Despite a moderate resolution (7.4 Å and 7.9 Å), the anomalous scattering from platinum and a model representation from a recently published structure enabled localization of seven cisplatin binding sites by anomalous difference Fourier maps. Comparison with NKA structures in the E1P conformation suggested two possible inhibitory mechanisms for cisplatin. Binding to Met151 can block the N-terminal pathway for transported cations, while binding to Met171 can hinder the interaction of cytoplasmic domains during the catalytic cycle.

Aarhus University Department of Molecular Biology and Genetics Gustav Wieds Vej 10C DK 8000 Aarhus Denmark

Centre for Membrane Pumps in Cells and Disease PUMPkin Danish National Research Foundation DK 8000 Aarhus Denmark

Department of Biomedicine Aarhus University Ole Worms Alle 6 DK 8000 Aarhus Denmark

Department of Biophysics Centre of the Region Haná for Biotechnological and Agricultural Research Faculty of Science Palacký University 17 listopadu 12 771 46 Olomouc Czech Republic

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