How calcium inhibits the magnesium‐dependent enzyme human phosphoserine phosphatase

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Abstract
The structure of the Mg2+‐dependent enzyme human phosphoserine phosphatase (HPSP) was exploited to examine the structural and functional role of the divalent cation in the active site of phosphatases. Most interesting is the biochemical observation that a Ca2+ ion inhibits the activity of HPSP, even in the presence of added Mg2+. The sixfold coordinated Mg2+ ion present in the active site of HPSP under normal physiological conditions, was replaced by a Ca2+ ion by using a crystallization condition with high concentration of CaCl2 (0.7 m). The resulting HPSP structure now shows a sevenfold coordinated Ca2+ ion in the active site that might explain the inhibitory effect of Ca2+ on the enzyme. Indeed, the Ca2+ ion in the active site captures both side‐chain oxygen atoms of the catalytic Asp20 as a ligand, while a Mg2+ ion ligates only one oxygen atom of this Asp residue. The bidentate character of Asp20 towards Ca2+ hampers the nucleophilic attack of one of the Asp20 side chain oxygen atoms on the phosphorus atom of the substrate phosphoserine.