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Abstract Ion-transport mechanisms evolve by changing ion-selectivity, such as switching from Na + to H + selectivity in secondary-active transporters or P-type-ATPases. Here we study primary-active transport via P-type ATPases using functional and structural analyses to demonstrate that four simultaneous residue substitutions transform the non-gastric H + /K + pump, a strict H + -dependent electroneutral P-type ATPase, into a bona fide Na + -dependent electrogenic Na + /K + pump. Conversion of a H + -dependent primary-active transporter into a Na + -dependent one provides a prototype for similar studies of ion-transport proteins. Moreover, we solve the structures of the wild-type non-gastric H + /K + pump, a suitable drug target to treat cystic fibrosis, and of its Na + /K + pump-mimicking mutant in two major conformations, providing insight on how Na + binding drives a concerted mechanism leading to Na + /K + pump phosphorylation.