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Na + ,K + -ATPase is the active ion transport system that maintains the electrochemical gradients for Na + and K + across the plasma membrane of most animal cells. Na + ,K + -ATPase is constituted by the association of two major subunits, a catalytic α and a glycosylated β subunit, both of which exist as different isoforms (in mammals known as α1, α2, α3, α4, β1, β2 and β3). Na + ,K + -ATPase α and β isoforms assemble in different combinations to produce various isozymes with tissue specific expression and distinct biochemical properties. Na + ,K + -ATPase α4β1 is only found in male germ cells of the testis and is mainly expressed in the sperm flagellum, where it plays a critical role in sperm motility and male fertility. Here, we report the molecular structure of Na + ,K + -ATPase α4β1 at 2.37 Å resolution in the ouabain-bound state and in the presence of beryllium fluoride. Overall, Na + ,K + -ATPase α4 structure exhibits the basic major domains of a P-Type ATPase, resembling Na + ,K + -ATPase α1, but has differences specific to its distinct sequence. Dissimilarities include the site where the inhibitor ouabain binds. Molecular simulations indicate that glycosphingolipids can bind to a putative glycosphingolipid binding site, which could potentially modulate Na + ,K + -ATPase α4 activity. This is the first experimental evidence for the structure of Na + ,K + -ATPase α4β1. These data provide a template that will aid in better understanding the function Na + ,K + -ATPase α4β1 and will be important for the design and development of compounds that can modulate Na + ,K + -ATPase α4 activity for the purpose of improving male fertility or to achieve male contraception.

Na + /K + -ATPase (NKA) is a plasma membrane ion-transporting protein involved in the generation and maintenance of Na + and K + gradients across the cell membrane, which can produce a driving force for the secondary transport of metabolic substrates. NKA also regulates intracellular calcium that is responsible for modulating numerous cellular processes, while it interacts with many other proteins and functions as a signal transducer, with several signaling pathways being involved. Thus, NKA has become an important target for the treatment of human diseases. Cardiac glycosides are well-known NKA inhibitors, of which (+)-digoxin or digoxin has been long used for the treatment of congestive heart failure. Also, digoxin has exhibited potential antitumor activity, by targeting directly HIF-1α, NKA, and NF-κB. Thus, the function of NKA in human cardiovascular diseases and cancer and the therapeutic effects of digoxin on these diseases are summarized in the present review, with the correlations among digoxin, NKA, cardiovascular diseases, and cancer being discussed. Presented herein are also the antitumor potential of monosaccharide cardiac glycoside analogues of digoxin, including (-)-cryptanoside A, (-)-oleandrin, (-)-ouabain, and (+)-strebloside. It is hoped that this contribution will provide some helpful information for the design and discovery of new cardiac glycoside-type therapeutic agents for the treatment of cardiovascular diseases and cancer., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)