Crystals of Na(+)/K(+)-ATPase with bound cisplatin

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  • Miroslav Huliciak, 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; 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. Electronic address: miroslavhuliciak@gmail.com., Unknown
  • Linda Reinhard, 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. Electronic address: linda.reinhard@ki.se.
  • ,
  • Mette Laursen, 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. Electronic address: mette.laursen@embl-hamburg.de.
  • ,
  • Natalya Fedosova
  • Poul Nissen
  • Martin Kubala, 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. Electronic address: mkubala@prfnw.upol.cz., Unknown

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 (7.4Å and 7.9Å), 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.

Original languageEnglish
JournalBiochemical Pharmacology
Volume92
Issue3
Pages (from-to)494-498
Number of pages5
ISSN0006-2952
DOIs
Publication statusPublished - 6 Sep 2014

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