Binding of cardiotonic steroids to Na <sup>+</sup> ,K <sup>+</sup> -ATPase in the E2P state
R. Kanai, Flemming Cornelius, Haruo Ogawa, K. Motoyama, Bente Vilsen, Chikashi Toyoshima
Abstract
Significance Cardiotonic steroids (CTSs) are specific inhibitors of Na + ,K + -ATPase and have been studied over a long period of time because of their potential therapeutic use in heart failure, hypertension, and cancers. Their affinities and binding kinetics are vastly different and seemingly rather inconsistent in the literature. Recent development of nonconventional CTSs with unexpected behaviors has revived interest in CTSs as potential drugs. In this report, we carried out a systematic study on various CTSs, including rostafuroxin and istaroxime, using kinetics and X-ray crystallography of their complexes with Na + ,K + -ATPase, and explain how CTSs block the reaction cycle and why such large differences in inhibitory behaviors arise. The analysis suggests how isoform specificity may be achieved in order to improve their clinical usability.