Crystals of Na(+)/K(+)-ATPase with bound cisplatin
Language English Country England, Great Britain Media print-electronic
Document type Journal Article, Research Support, Non-U.S. Gov't
PubMed
25199459
DOI
10.1016/j.bcp.2014.08.029
PII: S0006-2952(14)00519-X
Knihovny.cz E-resources
- Keywords
- Adverse effects, Binding sites, Cisplatin, Na(+)/K(+)-ATPase, Sodium pump, X-ray crystallography,
- MeSH
- Cisplatin adverse effects chemistry metabolism MeSH
- Protein Conformation MeSH
- Crystallography, X-Ray MeSH
- Methionine chemistry metabolism MeSH
- Models, Molecular MeSH
- Ouabain chemistry MeSH
- Sodium-Potassium-Exchanging ATPase antagonists & inhibitors chemistry metabolism MeSH
- Protein Structure, Tertiary MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
- Names of Substances
- Cisplatin MeSH
- Methionine MeSH
- Ouabain MeSH
- Sodium-Potassium-Exchanging ATPase MeSH
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.
References provided by Crossref.org
