Article (Scientific journals)
The C-terminal cavity of the Na,K-ATPase analyzed by docking and electrophysiology
Paulsen, P. A.; Jurkowski, Wiktor; Apostolov, R. et al.
2013In Molecular Membrane Biology, 30 (2), p. 195-205
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Keywords :
ATPase; drug development; molecular docking
Abstract :
[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.
Research center :
- Luxembourg Centre for Systems Biomedicine (LCSB): Bioinformatics Core (R. Schneider Group)
Disciplines :
Biochemistry, biophysics & molecular biology
Identifiers :
UNILU:UL-ARTICLE-2012-1253
Author, co-author :
Paulsen, P. A.;  Danish National Research Foundation > Centre for Membrane Pumps in Cells and Disease
Jurkowski, Wiktor ;  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
External co-authors :
yes
Language :
English
Title :
The C-terminal cavity of the Na,K-ATPase analyzed by docking and electrophysiology
Publication date :
2013
Journal title :
Molecular Membrane Biology
ISSN :
1464-5203
Publisher :
Taylor & Francis Ltd, Abingdon, United Kingdom
Volume :
30
Issue :
2
Pages :
195-205
Peer reviewed :
Peer Reviewed verified by ORBi
European Projects :
FP7 - 201924 - EDICT - EUROPEAN DRUG INITIATIVE ON CHANNELS AND TRANSPORTERS
Funders :
CE - Commission Européenne [BE]
Available on ORBilu :
since 29 May 2013

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