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Literature summary extracted from

  • Peti, W.; Page, R.
    Strategies to make protein serine/threonine (PP1, calcineurin) and tyrosine phosphatases (PTP1B) druggable Achieving specificity by targeting substrate and regulatory protein interaction sites (2015), Bioorg. Med. Chem., 23, 2781-2785 .
    View publication on PubMedView publication on EuropePMC

Inhibitors

EC Number Inhibitors Comment Organism Structure
3.1.3.16 cyclosporin A
-
 Homo sapiens
3.1.3.16 guanabenz a small molecule drug that specifically inhibits translation by blocking the activity of elongation factor 2alpha (eIF2alpha) phosphatases, specifically CreP:PP1 and GADD34:PP1 Homo sapiens
3.1.3.16 microcystin
-
 Homo sapiens
3.1.3.16 additional information toxins that bind and block the PP1 active site are lethal, thus, potential drugs that target PP1 must interact outside the PP1 active site. The REG1:PP1 holoenzyme (REG1 represents a PP1 regulatory protein that contains an RVxF-PhiPhi-Arg motif, such as PNUTS) is preferentially populated compared to the REG2:PP1 holoenzyme (REG2 is a PP1 regulatory protein with only an RVxF motif), because the affinity of REG1 for PP1 is much higher than REG2 for PP1. A drug that targets only the PhiPhi-Arg binding grooves will selectively displace the motifs in REG1 that bind at these sites, thereby reducing the affinity of REG1 for PP1 and, consequently, increase the likelihood of forming REG2:PP1 holoenzymes. In this way, dephosphorylation of REG1:PP1 substrates will decrease while REG2:PP1 holoenzymes will increase Homo sapiens
3.1.3.16 nodularin
-
 Homo sapiens
3.1.3.16 okadaic acid
-
 Homo sapiens
3.1.3.16 salubrinal a small molecule drug that specifically inhibits translation by blocking the activity of elongation factor 2alpha (eIF2alpha) phosphatases, specifically CreP:PP1 and GADD34:PP1 Homo sapiens
3.1.3.16 swine fever virus protein A238L an African swine fever virus protein, inhibits the enzyme not by blocking its active site, but instead by binding to calcineurin substrate recognition grooves, which blocks calcineurin from binding and dephosphorylating its substrates. A238L binds calcineurin via both a PxIxIT sequence and an LxVP sequence, overview Homo sapiens
3.1.3.16 tacrolimus i.e. FK506; i.e. FK506 Homo sapiens
3.1.3.16 tautomycin
-
 Homo sapiens
3.1.3.48 additional information the active sites of PTPs are exceptionally conserved and charged, making it nearly impossible to develop PTP inhibitors that are selective. But targeting PTP protein (substrate/regulatory) interaction sites, which are distal from the active sites, are highly viable and suitable drug targets. Domains outside PTP catalytic domains have also been demonstrated to directly alter PTP activity. Development of drugs that bind to intrinsically disordered regions of the enzyme, overview Homo sapiens
3.1.3.48 MSI-1436 small molecule inhibitor MSI-1436 binds to the disordered C-terminal domain of PTP1B, C-terminal to the catalytic domain, MSI-1436 functions using an allosteric mechanism to direct the enzymatic activity of PTP1B Homo sapiens

Metals/Ions

EC Number Metals/Ions Comment Organism Structure
3.1.3.16 Ca2+ required for enzyme activity Homo sapiens

Natural Substrates/ Products (Substrates)

EC Number Natural Substrates Organism Comment (Nat. Sub.) Natural Products Comment (Nat. Pro.) Rev. Reac.
3.1.3.16 [elongation factor 2alpha]-serine/threonine phosphate + H2O Homo sapiens
-
 [elongation factor 2alpha]-serine/threonine + phosphate
-
 ?
3.1.3.48 [a protein]-tyrosine phosphate + H2O Homo sapiens
-
 [a protein]-tyrosine + phosphate
-
 ?

Organism

EC Number Organism UniProt Comment Textmining
3.1.3.16 Homo sapiens P62136 catalytic subunit alpha
-
3.1.3.16 Homo sapiens Q08209 catalytic subunit alpha
-
3.1.3.48 Homo sapiens P18031
-
-

Substrates and Products (Substrate)

EC Number Substrates Comment Substrates Organism Products Comment (Products) Rev. Reac.
3.1.3.16 additional information although the specificity of the PP1 catalytic domains is low, PP1 dephosphorylates its substrates with high specificity. To achieve this, PP1 interacts with more than 100 distinct regulatory subunits, namely, inhibitory proteins that potently inhibit phosphatase activity by binding and blocking the active site, and targeting proteins, proteins that localize PP1 to distinct regions of the cell while also directly modulating PP1-substrate interactions. Many PP1 targeting subunits, such as NIPP1, enhance the binding of specific substrates. PP1 substrates bind directly to enzyme PP1, bind to other domains that are part of the PP1 regulatory proteins to enhance dephosphorylation or are dephosphorylated because PP1 is localized in proximity to the substrate via its targeting proteins Homo sapiens ?
-
 ?
3.1.3.16 additional information calcineurin is regulated by calcium, which is required for activation. Calcineurin binds directly to its substrates via protein interaction motifs that are also used by regulatory proteins Homo sapiens ?
-
 ?
3.1.3.16 [elongation factor 2alpha]-serine/threonine phosphate + H2O
-
 Homo sapiens [elongation factor 2alpha]-serine/threonine + phosphate
-
 ?
3.1.3.48 [a protein]-tyrosine phosphate + H2O
-
 Homo sapiens [a protein]-tyrosine + phosphate
-
 ?

Synonyms

EC Number Synonyms Comment Organism
3.1.3.16 calcineurin
-
 Homo sapiens
3.1.3.16 eIF2alpha phosphatase
-
 Homo sapiens
3.1.3.16 PP1
-
 Homo sapiens
3.1.3.16 protein phosphatase 1
-
 Homo sapiens
3.1.3.16 protein serine/threonine
-
 Homo sapiens
3.1.3.48 protein tyrosine phosphatase
-
 Homo sapiens
3.1.3.48 PTP1B
-
 Homo sapiens

General Information

EC Number General Information Comment Organism
3.1.3.16 malfunction toxins that bind and block the PP1 active site are lethal, thus, potential drugs that target PP1 must interact outside the PP1 active site Homo sapiens