Reaction scheme and structural detail of the Na⁺/K⁺-ATPase. (A) Modified Post-Albers reaction cycle of the Na⁺/K⁺-ATPase. Upon intracellular binding of Na⁺ ions to the E₁ conformation, a phosphointermediate with occluded Na⁺ ions, E₁P(3Na⁺), is formed, and after a conformational change to E₂P(3Na⁺), the Na⁺ ions dissociate to the extracellular space. Subsequently, two K⁺ ions bind from the extracellular side and become occluded, a process that stimulates dephosphorylation, and after a conformational change from E₂ to E₁, the K⁺ ions are intracellularly released. The gray box indicates the reaction sequence that can be studied by voltage pulses at high [Na⁺]_ext and [K⁺]_ext = 0 in TEVC experiments. (B) Structure of the Na⁺/K⁺-ATPase according to PDB structure entry 3B8E (Morth et al., 2007). Amino acids referred to in this work are indicated in ball-and-stick representation with numbering according to the human Na⁺/K⁺-ATPase α₂ subunit. Helix M5 is depicted in yellow, the backbone of the carboxy terminus (V¹⁰¹⁴-EKETY-Y¹⁰²⁰) is in red, and residues of a carboxy-terminal arginine cluster are in olive. Two Rb⁺ ions at the binding sites are shown as magenta spheres. Note that Arg¹⁰⁰⁵ in the 3B8E structure (pig renal α₁ subunit) corresponds to Tyr¹⁰⁰⁹ in the human Na⁺/K⁺-ATPase α₂ subunit.