{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,28]],"date-time":"2026-07-28T00:55:53Z","timestamp":1785200153816,"version":"3.55.0"},"reference-count":87,"publisher":"MDPI AG","issue":"24","license":[{"start":{"date-parts":[[2021,12,9]],"date-time":"2021-12-09T00:00:00Z","timestamp":1639008000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100006769","name":"Russian Science Foundation","doi-asserted-by":"publisher","award":["19-74-30007"],"award-info":[{"award-number":["19-74-30007"]}],"id":[{"id":"10.13039\/501100006769","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100006769","name":"Russian Science Foundation","doi-asserted-by":"publisher","award":["19-14-00374"],"award-info":[{"award-number":["19-14-00374"]}],"id":[{"id":"10.13039\/501100006769","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>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-sensitive (\u03b11S) and -resistant (\u03b11R) \u03b11-subunit, respectively. Marinobufagenin in contrast to ouabain and digoxin interacted with \u03b11S-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 \u03b11R-NKA induced the reduction in CTSs\u2019 steroid core deepening that led to the reversible inhibition of \u03b11R-NKA by ouabain and digoxin and the absence of marinobufagenin\u2019s effect on \u03b11R-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 \u03b11S-NKA) or the change of the width of CTSs-binding cavity (all CTSs in \u03b11R-NKA).<\/jats:p>","DOI":"10.3390\/ijms222413268","type":"journal-article","created":{"date-parts":[[2021,12,9]],"date-time":"2021-12-09T21:46:58Z","timestamp":1639086418000},"page":"13268","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["Depth of the Steroid Core Location Determines the Mode of Na,K-ATPase Inhibition by Cardiotonic Steroids"],"prefix":"10.3390","volume":"22","author":[{"given":"Artem M.","family":"Tverskoi","sequence":"first","affiliation":[{"name":"Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, 32 Vavilova Street, 119991 Moscow, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9710-7490","authenticated-orcid":false,"given":"Yuri M.","family":"Poluektov","sequence":"additional","affiliation":[{"name":"Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, 32 Vavilova Street, 119991 Moscow, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0978-8845","authenticated-orcid":false,"given":"Elizaveta A.","family":"Klimanova","sequence":"additional","affiliation":[{"name":"Faculty of Biology, Lomonosov Moscow State University, 1\/12 Leniskie Gory Street, 119234 Moscow, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1517-1983","authenticated-orcid":false,"given":"Vladimir A.","family":"Mitkevich","sequence":"additional","affiliation":[{"name":"Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, 32 Vavilova Street, 119991 Moscow, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexander A.","family":"Makarov","sequence":"additional","affiliation":[{"name":"Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, 32 Vavilova Street, 119991 Moscow, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sergei N.","family":"Orlov","sequence":"additional","affiliation":[{"name":"Faculty of Biology, Lomonosov Moscow State University, 1\/12 Leniskie Gory Street, 119234 Moscow, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Irina Yu.","family":"Petrushanko","sequence":"additional","affiliation":[{"name":"Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, 32 Vavilova Street, 119991 Moscow, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Olga D.","family":"Lopina","sequence":"additional","affiliation":[{"name":"Faculty of Biology, Lomonosov Moscow State University, 1\/12 Leniskie Gory Street, 119234 Moscow, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,12,9]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"36","DOI":"10.1016\/j.clinbiochem.2004.08.005","article-title":"A Novel Endogenous Digitalis, Telocinobufagin, Exhibits Elevated Plasma Levels in Patients with Terminal Renal Failure","volume":"38","author":"Komiyama","year":"2005","journal-title":"Clin. 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