Reference : The C-terminal cavity of the Na,K-ATPase analyzed by docking and electrophysiology
Scientific journals : Article
Life sciences : Biochemistry, biophysics & molecular biology
http://hdl.handle.net/10993/2301
The C-terminal cavity of the Na,K-ATPase analyzed by docking and electrophysiology
English
Paulsen, P. A. [Danish National Research Foundation > Centre for Membrane Pumps in Cells and Disease]
Jurkowski, Wiktor mailto [University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB) > > ; Stockholm University, Sweden > Center for Biomembrane Research]
Apostolov, R. [Stockholm University, Sweden > Center for Biomembrane Research]
Lindahl, E. [Stockholm University, Sweden > Center for Biomembrane Research]
Nissen, P. [Danish National Research Foundation > Centre for Membrane Pumps in Cells and Disease]
Poulsen, H. [Danish National Research Foundation > Centre for Membrane Pumps in Cells and Disease]
2013
Molecular Membrane Biology
Taylor & Francis Ltd
30
2
195-205
Yes (verified by ORBilu)
International
0968-7688
1464-5203
Abingdon
United Kingdom
[en] ATPase ; drug development ; molecular docking
[en] The Na,K-ATPase is essential to all animals, since it maintains the electrochemical gradients that energize the plasma membrane. Naturally occurring inhibitors of the pump from plants have been used pharmaceutically in cardiac treatment for centuries. The inhibitors block the pump by binding on its extracellular side and thereby locking it. To explore the possibilities for designing an alternative way of targeting the pump function, we have examined the structural requirements for binding to a pocket that accommodates the two C-terminal residues, YY, in the crystal structures of the pump. To cover the sample space of two residues, we first performed docking studies with the 400 possible dipeptides. For validation of the in silico predictions, pumps with 13 dipeptide sequences replacing the C-terminal YY were expressed in Xenopus laevis oocytes and examined with electrophysiology. Our data show a significant correlation between the docking scores from two different methods and the experimentally determined sodium affinities, which strengthens the previous hypothesis that sodium binding is coupled to docking of the C-terminus. From the dipeptides that dock the best and better than wild-type YY, it may therefore be possible to develop specific drugs targeting a previously unexplored binding pocket in the sodium pump.
Luxembourg Centre for Systems Biomedicine (LCSB): Bioinformatics Core (R. Schneider Group)
Researchers ; Professionals
http://hdl.handle.net/10993/2301
10.3109/09687688.2012.713520
FP7 ; 201924 - EDICT - EUROPEAN DRUG INITIATIVE ON CHANNELS AND TRANSPORTERS

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