Crystal structures and snapshots along the reaction pathway of human phosphoserine phosphatase

The equilibrium between phosphorylation and dephosphorylation is one of the
most important processes that takes place in living cells. Human phosphoserine
phosphatase (hPSP) is a key enzyme in the production of serine by the
dephosphorylation of phospho-l-serine. It is directly involved in the biosynthesis
of other important metabolites such as glycine and d-serine (a
neuromodulator). hPSP is involved in the survival mechanism of cancer cells
and has recently been found to be an essential biomarker. Here, three new highresolution crystal structures of hPSP (1.5–2.0 Ang.) in complexes with phosphoserine and with serine, which are the substrate and the product of the reaction, respectively, and in complex with a noncleavable substrate analogue (homocysteic acid) are presented. New types of interactions take place between the
enzyme and its ligands. Moreover, the loop involved in the open/closed state of
the enzyme is fully refined in a totally unfolded conformation. This loop is
further studied through molecular-dynamics simulations. Finally, all of these
analyses allow a more complete reaction mechanism for this enzyme to be
proposed which is consistent with previous publications on the subject.