Protein phosphatase, Mg2+/Mn2+ dependent 1D (PPM1D)

Protein phosphatase, Mg2+/Mn2+ dependent 1D (PPM1D) is a serine/threonine protein phosphatase belonging to the PP2C family. Induced by p53 in response to cellular stress and DNA damage, it acts as a negative regulator of DNA damage response pathways by dephosphorylating critical proteins such as p53 and CHEK1, thereby enabling cells to exit checkpoint arrests. PPM1D is central to a feedback loop controlling cell cycle progression, apoptosis suppression, and genome integrity; its amplification and gain-of-function mutations are implicated in multiple cancers, making it a recognized therapeutic target. The enzyme is also linked to rare neurodevelopmental disorders (e.g., Jansen-de Vries Syndrome) through pathogenic variants. Allosteric inhibitors such as GSK2830371 modulate the function of PPM1D by stabilizing inactive conformations, providing proof-of-concept for drug targeting in oncology. Safety concerns arise due to its broad roles in cell stress responses and potential effects on genomic stability.

Other names

PPM1DWild-type p53-induced phosphatase 1WIP1PP2C-deltaProtein phosphatase 2C isoform deltaProtein phosphatase 1D magnesium-dependent, delta isoformProtein phosphatase magnesium-dependent 1 deltaProtein phosphatase 1DProtein phosphatase, Mg2+/Mn2+ dependent 1DProtein serine/threonine phosphatase Wip1

Allosteric inhibition (e.g., GSK2830371 binds flap domain and locks PPM1D into inactive conformation) Non-competitive inhibition (drugs can alter conformation without directly blocking active site) Potential substrate-competitive or catalytic site targeting under investigation