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

被引：19

作者：

Huliciak, Miroslav ^{[1
,2
,3
]}

Reinhard, Linda ^{[2
,3
]}

Laursen, Mette ^{[3
]}

Fedosova, Natalya ^{[3
]}

Nissen, Poul ^{[2
,3
,4
]}

Kubala, Martin ^{[1
]}

机构：

[1] Palacky Univ, Fac Sci, Dept Biophys, Ctr Reg Hana Biotechnol & Agr Res, Olomouc 77146, Czech Republic

[2] Aarhus Univ, Dept Mol Biol & Genet, DK-8000 Aarhus, Denmark

[3] Danish Natl Res Fdn, Ctr Membrane Pumps Cells & Dis, PUMPkin, DK-8000 Aarhus, Denmark

[4] Aarhus Univ, Dept Biomed, DK-8000 Aarhus, Denmark

来源：

BIOCHEMICAL PHARMACOLOGY | 2014年 / 92卷 / 03期

关键词：

Adverse effects; Binding sites; Cisplatin; Na+/K+-ATPase; Sodium pump; X-ray crystallography; RETICULUM CA2+-ATPASE; ION PATHWAY; BINDING; MUTATIONS; NEPHROTOXICITY; PHOSPHOENZYME; NA; K-ATPASE; MECHANISMS; ROLES;

D O I：

10.1016/j.bcp.2014.08.029

中图分类号：

R9 [药学];

学科分类号：

1007 ;

摘要：

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 (NM), 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 angstrom and 7.9 angstrom), 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. (C) 2014 Elsevier Inc. All rights reserved.

引用

页码：494 / 498

页数：5

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