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ATP hydrolase acts as a transport protein, converting energy from ATP hydrolysis into transport molecules against their concentration gradients. In addition to energy metabolism and active transport, ATP hydrolase is essential for maintaining cellular homeostasis and cell function. This study focused on the domain architecture model of P\u2010type ATPases, which participate in the reaction cycles of ATP hydrolysis carried out by membrane transport systems \u2013 Na+, K+\u2010ATPase and Ca2+, Mg2+\u2010ATPase. Targeted modulation of Na+, K+\u2010ATPase and Ca2+, Mg2+\u2010ATPase by unnatural drugs is of greatest interest due to the lack of known effectors. This new discovery presents a convenient model based on our recent experimental studies of the membrane structures and myocytes of the uterine smooth muscle, the myometrium. This current study strongly supports the fact that nanosized calix[4]arenes functionalised on the upper rings of the macrocycle with biologically active phosphonic acid fragments can serve as selective and potent inhibitors of cation\u2010transporting electroenzymes. This is how we discovered that calix[4]arene of methylenebisphosphonic acid C\u201097 and calix[4]arene of bis\u2010aminophosphonic acid C\u2010107 selectively and effectively (I0.5 &lt;100\u2005nM) inhibit the activity of Mg2+, ATP\u2010dependent electrogenic Na+ K+ plasma membrane pump. As drug discovery in the field of Mg2+\u2010ATPase inhibitors is uncharted territory, basic research holds the key to explaining and predicting the mechanism of interaction and action of different classes of compounds. In light of the presented results, new calix[4]arene compounds can be used as potent inhibitors of Mg2+, ATP\u2010dependent electrogenic ion pumps.<\/jats:p>","DOI":"10.1002\/minf.202400200","type":"journal-article","created":{"date-parts":[[2024,12,5]],"date-time":"2024-12-05T05:44:44Z","timestamp":1733377484000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Structural Insight on the Selectivity of Calyx[4]Arene\u2010Based Inhibitors of Mg\n                    <sup>2+\u2212<\/sup>\n                    Dependent Atp\u2010Hydrolases"],"prefix":"10.1002","volume":"44","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7596-6294","authenticated-orcid":false,"given":"Alexey","family":"Rayevsky","sequence":"first","affiliation":[{"name":"Institute of Food Biotechnology and Genomics Natl. 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