Download MendeleyStructural insights into the high affinity binding of cardiotonic steroids to the Na+,K+-ATPase.
Yatime, L., Laursen, M., Morth, J.P., Esmann, M., Nissen, P., Fedosova, N.U.(2011) J Struct Biol 174: 296-306
- PubMed: 21182963
- DOI: https://doi.org/10.1016/j.jsb.2010.12.004
- Primary Citation of Related Structures:
3N23 - PubMed Abstract:
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 ? 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 ¦ÁM1-¦ÁM6, 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 ¦ÁM1-2 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.
Organizational Affiliation:
Centre for Membrane Pumps in Cells and Disease-PUMPKIN, Danish National Research Foundation, Denmark.
