Beneficent and Maleficent Effects of Cations on Bufadienolide Binding to Na+,K+-ATPase Lucy

Kinetic properties and crystal structures of the Na+,K+-ATPase in complex with cardiotonic steroids (CTS) revealed significant differences between CTS subfamilies (Laursen et al.). Thus, we found beneficial effects of K+ on bufadienolide binding, which strongly contrasted with the well-known antagonism between K+ and cardenolides. In order to understand this peculiarity of bufalin interactions, we used docking and molecular dynamics simulations of the complexes involving Na+,K+-ATPase, bufadienolides (bufalin, cinobufagin), and ions (K+, Na+, Mg2+). The results revealed that bufadienolide binding is affected by (i) electrostatic attraction of the lactone ring by a cation and (ii) the ability of a cation to stabilize and shape the site constituted by transmembrane helices of the alpha-subunit (alpha M1-6). The latter effect was due to varying coordination patterns involving amino acid residues from helix bundles alpha M1-4 and alpha M5-10. Substituents on the steroid core of a bufadienolide add to and modify the cation effects. The above rationale is fully consistent with the ion effects on the kinetics of Na+,K+-ATPase/bufadienolide interactions.

Automated summary

The study reveals significant differences in the binding properties of different subfamilies of cardiotonic steroids with the Na+,K+-ATPase. While bufadienolides show beneficial effects with K+, they differ from cardenolides which have an antagonistic relationship with K+. Through simulations, it was found that the binding of bufadienolides is influenced by amino acid coordination patterns and the presence of cations, illustrating the complex interplay of factors in these interactions.