1. Depth of the Steroid Core Location Determines the Mode of Na,K-ATPase Inhibition by Cardiotonic Steroids.
- Author
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Tverskoi AM, Poluektov YM, Klimanova EA, Mitkevich VA, Makarov AA, Orlov SN, Petrushanko IY, and Lopina OD
- Subjects
- Animals, Binding Sites, Cardiac Glycosides pharmacology, Hydrogen Bonding, Kidney drug effects, Models, Molecular, Protein Binding, Protein Conformation, Rats, Sodium-Potassium-Exchanging ATPase chemistry, Swine, Bufanolides pharmacology, Digoxin pharmacology, Kidney enzymology, Ouabain pharmacology, Sodium-Potassium-Exchanging ATPase metabolism
- Abstract
Cardiotonic steroids (CTSs) are specific inhibitors of Na,K-ATPase (NKA). They induce diverse physiological effects and were investigated as potential drugs in heart diseases, hypertension, neuroinflammation, antiviral and cancer therapy. Here, we compared the inhibition mode and binding of CTSs, such as ouabain, digoxin and marinobufagenin to NKA from pig and rat kidneys, containing CTSs- s ensitive (α1 S ) and - r esistant (α1 R ) α1-subunit, respectively. Marinobufagenin in contrast to ouabain and digoxin interacted with α1S-NKA reversibly, and its binding constant was reduced due to the decrease in the deepening in the CTSs-binding site and a lower number of contacts between the site and the inhibitor. The formation of a hydrogen bond between Arg111 and Asp122 in α1R-NKA induced the reduction in CTSs' steroid core deepening that led to the reversible inhibition of α1R-NKA by ouabain and digoxin and the absence of marinobufagenin's effect on α1R-NKA activity. Our results elucidate that the difference in signaling, and cytotoxic effects of CTSs may be due to the distinction in the deepening of CTSs into the binding side that, in turn, is a result of a bent-in inhibitor steroid core (marinobufagenin in α1S-NKA) or the change of the width of CTSs-binding cavity (all CTSs in α1R-NKA).
- Published
- 2021
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