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The C-terminal cavity of the Na,K-ATPase analyzed by docking and electrophysiology

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  • Peter Aasted Paulsen, Denmark
  • Wiktor Jurkowski, Center for Biomembrane Research, Department of Biochemistry & Biophysics, Stockholm University, Sweden
  • Rossen Apostolov, Swedish e-Science Research Center, Department of Theoretical Physics, Royal Institute of Technology, Sweden
  • Erik Lindahl, Center for Biomembrane Research, Department of Biochemistry & Biophysics, Stockholm University, Sweden
  • Poul Nissen
  • Hanne Poulsen
Abstract 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.
Original languageEnglish
JournalMolecular Membrane Biology
Volume30
Issue2
Pages (from-to)195-205
Number of pages11
ISSN0968-7688
DOIs
Publication statusPublished - Mar 2013

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