Na,K-ATPase as drug target

Group leader: ass.prof. Natalya Fedosova

Current interests

1) Structural aspects of specific protein-ligand interactions including crystallization
2) Mechanism of coupling of ATP hydrolysis to cation transport
3) Inhibitor binding to the Na+,K+-ATPase
4) Lipid-protein interactions and protein stability

Fields of expertise

Isolation and purification of membrane-bound proteins, solubilisation in the functionally active state, biochemical characterisation of the purified proteins with respect to their quaternary structure and functional properties.

Methods

Analytical ultracentrifugation, gel chromatography, HPLC, MALS, electrophoresis, absorbance and fluorescence spectroscopy, conventional biochemical methods for the study of the transprot mechanism of P-type ATPases.

Publications

  1. Nyblom, M., Poulsen, H., Gourdon, P., Reinhard, L., Andersson, M., Lindahl, E., Fedosova, N.U., and Nissen, P. (2013) Crystal structure of Na,K-ATPase in the Na+-bound state. Science 342, 6154, 123-127.  
  2. Laursen, M., Yatime, L., Nissen, P., and  Fedosova, N. U. (2013) Crystal structure of the high-affinity Na+,K+-ATPase–ouabain complex with Mg2+ bound in the cation binding site. Proc. Natl. Acad. Sci.  110, 27 10958-10963.
  3. Miles, A.J., Fedosova, N.U., Hoffmann, S.V., Wallace, B.A., and Esmann, M. (2013) Stabilisation of Na,K-ATPase structure by the cardiotonic steroid ouabain. Biochem.Biophys.Res.Com. 435, 300-305.
  4. Weigand, K.M., Swarts, H.G.P., Fedosova, N.U., Russel, F.G.M., and Koenderink, J.B. (2012) Na,K-ATPase activity modulates Src activation: A role for ATP/ADP ratio. Biochem. Biophys. Acta1818, 5, 1269–1273.
  5. Fedosov, S.N., Ruetz, M., Gruber, K., Fedosova, N.U., and Kräutler, B. (2011) A blue corrinoid from partial degradation of vitamin B(12) in aqueous bicarbonate: spectra, structure, and interaction with proteins of B(12) transport. Biochemistry 50, 8090-8101.
  6. Hansen, A.S., Kraglund, K.L., Fedosova, N.U., and Esmann, M.  (2011) Bulk properties of the lipid bilayer are not essential for the thermal stability of Na,K-ATPase from shark rectal gland or pig kidney. Biochim. Biophys. Res. Commun. 406, 580-583.
  7. Mangialavori, I., Montes, M.R., Rossi, R.C., Fedosova, N.U., and Rossi, J.P.F.C. (2011)  Dynamic protein-lipid stoichiometry on E1 and E2 conformations of the Na+/K+-ATPase. FEBS Lett. 585, 1153-1157.
  8. Jensen, M., Schmidt, S., Fedosova, N.U., Mollenhauer, J., and Jensen, H.H. (2011) Synthesis and Evaluation of Cardiac Glycosides Mimics as Potential Anticancer Drugs.  Bioorg. Med. Chem. 19, 2407-2417.
  9. Yatime, L., Laursen, M., Morth, J.P., Esmann, M., Nissen, P., and Fedosova N.U. (2011) "Structural insights into the high affinity binding of cardiotonic steroids to the Na+,K+- ATPase".  J.Struct.Biol. 174, 296-306.
  10. Faxén, K., Andersen, J.L., Gourdon, P., Fedosova, N.U., Morth, J.P., Nissen, P., and Møller, J.V. (2011) Characterization of the Listeria monocytogenes Ca2+-pump - a SERCA-type ATPase with only one Ca2+-binding site. J.Biol.Chem. 286, 1609-1617.
  11. Mohammad, B., Esmann, M., Fedosova, N.U., and Marsh, D. (2009) Urea-Induced Unfolding of Na,K-ATPase As Evaluated by Electron Paramagnetic Resonance Spectroscopy. Biochemistry 48, 9022-9030.
  12. Middleton, D.A., Hughes, E., Fedosova, N.U., and Esmann, M. (2009) Solid-State NMR Studies of Adenosine 5’-Triphosphate Freeze-Trapped in the Nucleotide Site of Na,K-ATPase. ChemBioChem 10, 1789-1792. 
  13. Yatime, L., Buch-Pedersen, M.J., Musgaard, M., Morth, J.P., Winter, A.-M.L., Pedersen, B.P., Olesen, C., Andersen, J.P., Vilsen, B., Schøtt, B., Palmgren, M.G., Møller, J.V., Nissen, P., and Fedosova N.U. (2009) P-type ATPases as drug targets: Tools for medicine and science. Biochim. Biophys.Acta 178, 207-220.