Abstract
The usage and the potential for toxic side effects of cardiac glycosides are still hot topics for discussion and these compounds still remain important clinical components for the treatment of congestive heart failure. Understanding the mechanism of binding of cardiac glycosides to the Na,K-ATPase remains incomplete. We use a combination of the most recently discovered crystal structures of Na,K-ATPase together with the available kinetic and mutagenesis data to give a reasonable explanation of the basis of binding of cardiac glycosides to the Na,K-ATPase, in particular addressing the following questions: (1) why cardiac glycosides bind more strongly to phosphorylated forms of the enzyme than unphosphorylated forms, (2) does Mg2+ have any effect on stabilizing the ouabain-enzyme complex in the phosphorylated form, (3) do Na+, K+ and ATP play any roles in strengthening the interaction of ouabain with the Na,K-ATPase, and (4) are there any site-site interactions between ouabain and the protein's ligand binding sites.