Résumé

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.
langue originaleAnglais
Pages (de - à)592-604
journalActa Crystallographica Section D: Biological Crystallography
Volume75
étatPublié - 2019

Empreinte digitale

Serine
Enzymes
Phosphoserine
Molecular Dynamics Simulation
Glycine
Biomarkers
Phosphorylation
Ligands
Survival
phosphoserine phosphatase
Neoplasms

Citer ceci

@article{92fec186dc8242e2ad9d995831b13407,
title = "Crystal structures and snapshots along the reaction pathway of human phosphoserine phosphatase",
abstract = "The equilibrium between phosphorylation and dephosphorylation is one of themost important processes that takes place in living cells. Human phosphoserinephosphatase (hPSP) is a key enzyme in the production of serine by thedephosphorylation of phospho-l-serine. It is directly involved in the biosynthesisof other important metabolites such as glycine and d-serine (aneuromodulator). hPSP is involved in the survival mechanism of cancer cellsand 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 theenzyme and its ligands. Moreover, the loop involved in the open/closed state ofthe enzyme is fully refined in a totally unfolded conformation. This loop isfurther studied through molecular-dynamics simulations. Finally, all of theseanalyses allow a more complete reaction mechanism for this enzyme to beproposed which is consistent with previous publications on the subject.",
keywords = "phosphoserine phosphatase; mechanism; cancer.",
author = "Marie Haufroid and Manon Mirgaux and Laurence Leherte and Johan Wouters",
year = "2019",
language = "English",
volume = "75",
pages = "592--604",
journal = "Acta Crystallographica Section D: Biological Crystallography",
issn = "0907-4449",
publisher = "International Union of Crystallography",

}

TY - JOUR

T1 - Crystal structures and snapshots along the reaction pathway of human phosphoserine phosphatase

AU - Haufroid, Marie

AU - Mirgaux, Manon

AU - Leherte, Laurence

AU - Wouters, Johan

PY - 2019

Y1 - 2019

N2 - The equilibrium between phosphorylation and dephosphorylation is one of themost important processes that takes place in living cells. Human phosphoserinephosphatase (hPSP) is a key enzyme in the production of serine by thedephosphorylation of phospho-l-serine. It is directly involved in the biosynthesisof other important metabolites such as glycine and d-serine (aneuromodulator). hPSP is involved in the survival mechanism of cancer cellsand 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 theenzyme and its ligands. Moreover, the loop involved in the open/closed state ofthe enzyme is fully refined in a totally unfolded conformation. This loop isfurther studied through molecular-dynamics simulations. Finally, all of theseanalyses allow a more complete reaction mechanism for this enzyme to beproposed which is consistent with previous publications on the subject.

AB - The equilibrium between phosphorylation and dephosphorylation is one of themost important processes that takes place in living cells. Human phosphoserinephosphatase (hPSP) is a key enzyme in the production of serine by thedephosphorylation of phospho-l-serine. It is directly involved in the biosynthesisof other important metabolites such as glycine and d-serine (aneuromodulator). hPSP is involved in the survival mechanism of cancer cellsand 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 theenzyme and its ligands. Moreover, the loop involved in the open/closed state ofthe enzyme is fully refined in a totally unfolded conformation. This loop isfurther studied through molecular-dynamics simulations. Finally, all of theseanalyses allow a more complete reaction mechanism for this enzyme to beproposed which is consistent with previous publications on the subject.

KW - phosphoserine phosphatase; mechanism; cancer.

M3 - Article

VL - 75

SP - 592

EP - 604

JO - Acta Crystallographica Section D: Biological Crystallography

JF - Acta Crystallographica Section D: Biological Crystallography

SN - 0907-4449

ER -