Structural insights into the high affinity binding of cardiotonic steroids to the Na+,K+-ATPase

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The Na+,K+-ATPase belongs to the P-ATPase family, whose characteristic property is the formation of a phosphorylated intermediate. The enzyme is also a defined target for cardiotonic steroids which inhibit its functional activity and initiate intracellular signaling. Here we describe the 4.6 Å resolution crystal structure of the pig kidney Na+,K+-ATPase in its phosphorylated form stabilized by high affinity binding of the cardiotonic steroid ouabain. The steroid binds to a site formed at transmembrane segments αM1-αM6, plugging the ion pathway from the extracellular side. This structure differs from the previously reported low affinity complex with potassium. Most importantly, the A domain has rotated in response to phosphorylation and αM1-2 move towards the ouabain molecule, providing for high affinity interactions and closing the ion pathway from the extracellular side. The observed re-arrangements of the Na+,K+-ATPase stabilized by cardiotonic steroids may affect protein-protein interactions within the intracellular signal transduction networks.
Original languageEnglish
JournalJournal of Structural Biology
Pages (from-to)296-306
Number of pages11
Publication statusPublished - 2011

    Research areas

  • Animals, Binding Sites, Cardiotonic Agents, Crystallography, X-Ray, Magnesium, Models, Molecular, Ouabain, Phosphorylation, Protein Binding, Protein Structure, Secondary, Protein Structure, Tertiary, Sodium-Potassium-Exchanging ATPase, Swine

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