ArticleProceedings of the National Academy of Sciences of the United States of America2015
Structures and characterization of digoxin- and bufalin-bound Na+,K+-ATPase compared with the ouabain-bound complex.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 117 papers.
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Who cites it
117 citing papers in PubMed, 228 citations in OpenAlex.
- Discovery of Ro 41-0960, a Non-Steroidal Inhibitor of the NaChemMedChem · 2026Article
- Cardiac Glycoside 3β-Bufalin Suppresses Cancer Cell Proliferation by Coupling with NaInternational journal of molecular sciences · 2026Article
- Active conformations of neuronal NaNature communications · 2026Article
- Impact of Time, Temperature, and Conformational Changes on the Characterization of Cardiotonic Steroid-NaThe Journal of membrane biology · 2026Review
- The Na/K-ATPase α1 subunit fine-tunes platelet P2Y12 function and mediates sex dimorphism-associated thrombosis.Blood advances · 2026Article
- Article
- The mechanism of action of digoxin requires the sodium-dependent inactivation of the sodium-calcium exchanger.Science advances · 2025Article
- Rotation Conformational Effects of Selected Cytotoxic Cardiac Glycosides on Their Interactions with NaMolecules (Basel, Switzerland) · 2025Article
- Dual Modulation of Cardiac Ion Pumps: A Small-Molecule SERCA2a SUMOylation Enhancer Also Inhibits the NaBiomedicines · 2025Article
- Derivatization of Bufadienolides at Carbon-3 of the Steroid Core and Their Consequences for the Interaction with NaInternational journal of molecular sciences · 2025Article
- The role of Na,K‑ATPase in lung diseases (Review).Molecular medicine reports · 2025Review
- How palytoxin transforms the NaProceedings of the National Academy of Sciences of the United States of America · 2025Article
- Natural Product-Derived Drugs: Structural Insights into Their Biological Mechanisms.Biomolecules · 2025Review
- Elucidating the Complex Structural and Molecular Mechanisms Driving P-Glycoprotein-Mediated Transport of Cardiac Glycosides.International journal of molecular sciences · 2025Article
- Evolutionary insights into NaBMC ecology and evolution · 2025Article
- Electrophysiology Models for End-Stage Renal Disease Maladaptations That Promote Asystole.Reviews in cardiovascular medicine · 2025Review
- Bufalin Ameliorates Myocardial Ischemia/Reperfusion Injury by Suppressing Macrophage Pyroptosis via P62 Pathway.Journal of cardiovascular translational research · 2025Article
- Epidemiological patterns and therapeutic approaches of toad toxin poisoning in a retrospective case study.Scientific reports · 2025Review
- Evaluation of the neuroprotective potential of benzylidene digoxin 15 against oxidative stress in a neuroinflammation models induced by lipopolysaccharide and on neuronal differentiation of hippocampal neural precursor cells.Frontiers in pharmacology · 2025Article
- Mechanisms mediating effects of cardiotonic steroids in mammalian blood cells.Frontiers in pharmacology · 2025Review
57 more citing papers are in PubMed but not listed here.
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Authors and funding
5 authors at 3 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Cardiotonic steroids (CTSs) are specific and potent inhibitors of the Na(+),K(+)-ATPase, with highest affinity to the phosphoenzyme (E2P) forms. CTSs are comprised of a steroid core, which can be glycosylated, and a varying number of substituents, including a five- or six-membered lactone. These functionalities have specific influence on the binding properties. We report crystal structures of the Na(+),K(+)-ATPase in the E2P form in complex with bufalin (a nonglycosylated CTS with a six-membered lactone) and digoxin (a trisaccharide-conjugated CTS with a five-membered lactone) and compare their characteristics and binding kinetics with the previously described E2P-ouabain complex to derive specific details and the general mechanism of CTS binding and inhibition. CTSs block the extracellular cation exchange pathway, and cation-binding sites I and II are differently occupied: A single Mg(2+) is bound in site II of the digoxin and ouabain complexes, whereas both sites are occupied by K(+) in the E2P-bufalin complex. In all complexes, αM4 adopts a wound form, characteristic for the E2P state and favorable for high-affinity CTS binding. We conclude that the occupants of the cation-binding site and the type of the lactone substituent determine the arrangement of αM4 and hypothesize that winding/unwinding of αM4 represents a trigger for high-affinity CTS binding. We find that the level of glycosylation affects the depth of CTS binding and that the steroid core substituents fine tune the configuration of transmembrane helices αM1-2.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.