Target Information

Target General Information

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Target ID

T40491 (Former ID: TTDI00641)

Target Name

Serine/threonine PP2A-alpha (PPP2CA)

Synonyms

Serine/threonine-protein phosphatase 2A catalytic subunit alpha isoform; Replication protein C; RP-C; PP2A-alpha

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Gene Name

PPP2CA

Target Type

Clinical trial target

[1]

Disease

[+] 1 Target-related Diseases

Molluscum contagiosum [ICD-11: 1E76]

Function

PP2A can modulate the activity of phosphorylase B kinase casein kinase 2, mitogen-stimulated S6 kinase, and MAP-2 kinase. Cooperates with SGO2 to protect centromeric cohesin from separase-mediated cleavage in oocytes specifically during meiosis I. Can dephosphorylate SV40 large T antigen and p53/TP53. Activates RAF1 by dephosphorylating it at 'Ser-259'. PP2A is the major phosphatase for microtubule-associated proteins (MAPs).

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BioChemical Class

Phosphoric monoester hydrolase

UniProt ID

PP2AA_HUMAN

EC Number

EC 3.1.3.16

Sequence

MDEKVFTKELDQWIEQLNECKQLSESQVKSLCEKAKEILTKESNVQEVRCPVTVCGDVHG
QFHDLMELFRIGGKSPDTNYLFMGDYVDRGYYSVETVTLLVALKVRYRERITILRGNHES
RQITQVYGFYDECLRKYGNANVWKYFTDLFDYLPLTALVDGQIFCLHGGLSPSIDTLDHI
RALDRLQEVPHEGPMCDLLWSDPDDRGGWGISPRGAGYTFGQDISETFNHANGLTLVSRA
HQLVMEGYNWCHDRNVVTIFSAPNYCYRCGNQAAIMELDDTLKYSFLQFDPAPRRGEPHV
TRRTPDYFL

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3D Structure

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PDB

Drugs and Modes of Action

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Clinical Trial Drug(s)

[+] 2 Clinical Trial Drugs

VP-102

Drug Info

Phase 3

Molluscum contagiosum infection

[2]

LB-100

Drug Info

Phase 2

Astrocytoma

[3]

Mode of Action

[+] 1 Modes of Action

Inhibitor

[+] 2 Inhibitor drugs

VP-102

Drug Info

[1]

LB-100

Drug Info

[4]

Cell-based Target Expression Variations

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Cell-based Target Expression Variations

Cell-based Target Expression Variations Info

Drug Binding Sites of Target

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Ligand Name: Okadaic acid

Ligand Info

Structure Description

Structure of the Protein Phosphatase 2A Core Enzyme Bound to okadaic acid

PDB:2IE4

Method

X-ray diffraction

Resolution

2.60 Å

Mutation

[5]

PDB Sequence

FTKELDQWIE

¹⁵

QLNECKQLSE

²⁵

SQVKSLCEKA

³⁵

KEILTKESNV

⁴⁵

QEVRCPVTVC

⁵⁵

GDVHGQFHDL

⁶⁵

MELFRIGGKS

⁷⁵

PDTNYLFMGD

⁸⁵

YVDRGYYSVE

⁹⁵

TVTLLVALKV

¹⁰⁵

RYRERITILR

¹¹⁵

GNHESRQITQ

¹²⁵

VYGFYDECLR

¹³⁵

KYGNANVWKY

¹⁴⁵

FTDLFDYLPL

¹⁵⁵

TALVDGQIFC

¹⁶⁵

LHGGLSPSID

¹⁷⁵

TLDHIRALDR

¹⁸⁵

LQEVPHEGPM

¹⁹⁵

CDLLWSDPDD

²⁰⁵

RGGWGISPRG

²¹⁵

AGYTFGQDIS

²²⁵

ETFNHANGLT

²³⁵

LVSRAHQLVM

²⁴⁵

EGYNWCHDRN

²⁵⁵

VVTIFSAPNY

²⁶⁵

CYRCGNQAAI

²⁷⁵

MELDDTLKYS

²⁸⁵

FLQFDPAP

Residue

Distance (Å)

ARG89

2.713

ASN117

4.892

HIS118

3.325

GLN122

3.972

ILE123

3.914

TYR127

3.573

PRO190

4.883

HIS191

3.443

CYS196

4.925

TRP200

3.608

Residue

Distance (Å)

PRO213

3.369

ARG214

2.953

GLY215

4.421

ALA216

3.924

LEU243

3.469

TYR265

3.031

CYS266

3.969

ARG268

3.697

CYS269

3.837

Ligand Name: 35-Methylokadaic acid

Ligand Info

Structure Description

Protein phosphatase 2A core complex bound to dinophysistoxin-1

PDB:3K7V

Method

X-ray diffraction

Resolution

2.85 Å

Mutation

[6]

PDB Sequence

FTKELDQWIE

¹⁵

QLNECKQLSE

²⁵

SQVKSLCEKA

³⁵

KEILTKESNV

⁴⁵

QEVRCPVTVC

⁵⁵

GDVHGQFHDL

⁶⁵

MELFRIGGKS

⁷⁵

PDTNYLFMGD

⁸⁵

YVDRGYYSVE

⁹⁵

TVTLLVALKV

¹⁰⁵

RYRERITILR

¹¹⁵

GNHESRQITQ

¹²⁵

VYGFYDECLR

¹³⁵

KYGNANVWKY

¹⁴⁵

FTDLFDYLPL

¹⁵⁵

TALVDGQIFC

¹⁶⁵

LHGGLSPSID

¹⁷⁵

TLDHIRALDR

¹⁸⁵

LQEVPHEGPM

¹⁹⁵

CDLLWSDPDD

²⁰⁵

RGGWGISPRG

²¹⁵

AGYTFGQDIS

²²⁵

ETFNHANGLT

²³⁵

LVSRAHQLVM

²⁴⁵

EGYNWCHDRN

²⁵⁵

VVTIFSAPNY

²⁶⁵

CYRCGNQAAI

²⁷⁵

MELDDTLKYS

²⁸⁵

FLQFDPAP

Residue

Distance (Å)

ARG89

2.707

ASN117

4.927

HIS118

3.356

GLN122

3.454

ILE123

3.726

VAL126

4.998

TYR127

3.484

PRO190

4.772

HIS191

3.587

TRP200

3.609

Residue

Distance (Å)

PRO213

3.274

ARG214

3.242

GLY215

4.383

ALA216

3.933

LEU243

3.567

TYR265

3.209

CYS266

3.843

ARG268

3.973

CYS269

3.797

Click to View More Binding Site Information of This Target with Different Ligands

Different Human System Profiles of Target	Top
Human Similarity Proteins of target is determined by comparing the sequence similarity of all human proteins with the target based on BLAST. The similarity proteins for a target are defined as the proteins with E-value < 0.005 and outside the protein families of the target. A target that has fewer human similarity proteins outside its family is commonly regarded to possess a greater capacity to avoid undesired interactions and thus increase the possibility of finding successful drugs (Brief Bioinform, 21: 649-662, 2020). Human Tissue Distribution of target is determined from a proteomics study that quantified more than 12,000 genes across 32 normal human tissues. Tissue Specificity (TS) score was used to define the enrichment of target across tissues. The distribution of targets among different tissues or organs need to be taken into consideration when assessing the target druggability, as it is generally accepted that the wider the target distribution, the greater the concern over potential adverse effects (Nat Rev Drug Discov, 20: 64-81, 2021). Human Pathway Affiliation of target is determined by the life-essential pathways provided on KEGG database. The target-affiliated pathways were defined based on the following two criteria (a) the pathways of the studied target should be life-essential for both healthy individuals and patients, and (b) the studied target should occupy an upstream position in the pathways and therefore had the ability to regulate biological function. Targets involved in a fewer pathways have greater likelihood to be successfully developed, while those associated with more human pathways increase the chance of undesirable interferences with other human processes (Pharmacol Rev, 58: 259-279, 2006). Biological Network Descriptors of target is determined based on a human protein-protein interactions (PPI) network consisting of 9,309 proteins and 52,713 PPIs, which were with a high confidence score of ≥ 0.95 collected from STRING database. The network properties of targets based on protein-protein interactions (PPIs) have been widely adopted for the assessment of target’s druggability. Proteins with high node degree tend to have a high impact on network function through multiple interactions, while proteins with high betweenness centrality are regarded to be central for communication in interaction networks and regulate the flow of signaling information (Front Pharmacol, 9, 1245, 2018; Curr Opin Struct Biol. 44:134-142, 2017). Human Similarity Proteins Human Tissue Distribution Human Pathway Affiliation Biological Network Descriptors

Different Human System Profiles of Target

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Human Similarity Proteins of target is determined by comparing the sequence similarity of all human proteins with the target based on BLAST. The similarity proteins for a target are defined as the proteins with E-value < 0.005 and outside the protein families of the target.

A target that has fewer human similarity proteins outside its family is commonly regarded to possess a greater capacity to avoid undesired interactions and thus increase the possibility of finding successful drugs (Brief Bioinform, 21: 649-662, 2020).

Human Tissue Distribution of target is determined from a proteomics study that quantified more than 12,000 genes across 32 normal human tissues. Tissue Specificity (TS) score was used to define the enrichment of target across tissues.

The distribution of targets among different tissues or organs need to be taken into consideration when assessing the target druggability, as it is generally accepted that the wider the target distribution, the greater the concern over potential adverse effects (Nat Rev Drug Discov, 20: 64-81, 2021).

Human Pathway Affiliation of target is determined by the life-essential pathways provided on KEGG database. The target-affiliated pathways were defined based on the following two criteria (a) the pathways of the studied target should be life-essential for both healthy individuals and patients, and (b) the studied target should occupy an upstream position in the pathways and therefore had the ability to regulate biological function.

Targets involved in a fewer pathways have greater likelihood to be successfully developed, while those associated with more human pathways increase the chance of undesirable interferences with other human processes (Pharmacol Rev, 58: 259-279, 2006).

Biological Network Descriptors of target is determined based on a human protein-protein interactions (PPI) network consisting of 9,309 proteins and 52,713 PPIs, which were with a high confidence score of ≥ 0.95 collected from STRING database.

The network properties of targets based on protein-protein interactions (PPIs) have been widely adopted for the assessment of target’s druggability. Proteins with high node degree tend to have a high impact on network function through multiple interactions, while proteins with high betweenness centrality are regarded to be central for communication in interaction networks and regulate the flow of signaling information (Front Pharmacol, 9, 1245, 2018; Curr Opin Struct Biol. 44:134-142, 2017).

Human Similarity Proteins

Human Tissue Distribution

Human Pathway Affiliation

Biological Network Descriptors

There is no similarity protein (E value < 0.005) for this target


Note: If a protein has TS (tissue specficity) scores at least in one tissue >= 2.5, this protein is called tissue-enriched (including tissue-enriched-but-not-specific and tissue-specific). In the plots, the vertical lines are at thresholds 2.5 and 4.

KEGG Pathway	Pathway ID	Affiliated Target
mRNA surveillance pathway	hsa03015	Affiliated Target
Class: Genetic Information Processing => Translation	Pathway Hierarchy
Sphingolipid signaling pathway	hsa04071	Affiliated Target
Class: Environmental Information Processing => Signal transduction	Pathway Hierarchy
Oocyte meiosis	hsa04114	Affiliated Target
Class: Cellular Processes => Cell growth and death	Pathway Hierarchy
Autophagy - other	hsa04136	Affiliated Target
Class: Cellular Processes => Transport and catabolism	Pathway Hierarchy
Autophagy - animal	hsa04140	Affiliated Target
Class: Cellular Processes => Transport and catabolism	Pathway Hierarchy
PI3K-Akt signaling pathway	hsa04151	Affiliated Target
Class: Environmental Information Processing => Signal transduction	Pathway Hierarchy
AMPK signaling pathway	hsa04152	Affiliated Target
Class: Environmental Information Processing => Signal transduction	Pathway Hierarchy
Adrenergic signaling in cardiomyocytes	hsa04261	Affiliated Target
Class: Organismal Systems => Circulatory system	Pathway Hierarchy
TGF-beta signaling pathway	hsa04350	Affiliated Target
Class: Environmental Information Processing => Signal transduction	Pathway Hierarchy
Hippo signaling pathway	hsa04390	Affiliated Target
Class: Environmental Information Processing => Signal transduction	Pathway Hierarchy
Tight junction	hsa04530	Affiliated Target
Class: Cellular Processes => Cellular community - eukaryotes	Pathway Hierarchy
Dopaminergic synapse	hsa04728	Affiliated Target
Class: Organismal Systems => Nervous system	Pathway Hierarchy
Long-term depression	hsa04730	Affiliated Target
Class: Organismal Systems => Nervous system	Pathway Hierarchy
Click to Show/Hide the Information of Affiliated Human Pathways

Degree	60	Degree centrality	6.45E-03	Betweenness centrality	4.20E-03
Closeness centrality	2.47E-01	Radiality	1.43E+01	Clustering coefficient	1.50E-01
Neighborhood connectivity	2.33E+01	Topological coefficient	4.45E-02	Eccentricity	11
Download	Click to Download the Full PPI Network of This Target

Chemical Structure based Activity Landscape of Target

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Target Poor or Non Binders

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Target Poor or Non Binders

Target Poor or Non Binders Info

Target Regulators

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Target-interacting Proteins

Target-interacting Proteins Info

Target Affiliated Biological Pathways		Top
KEGG Pathway	[+] 13 KEGG Pathways	+
1	mRNA surveillance pathway
2	Sphingolipid signaling pathway
3	Oocyte meiosis
4	PI3K-Akt signaling pathway
5	AMPK signaling pathway
6	Adrenergic signaling in cardiomyocytes
7	TGF-beta signaling pathway
8	Hippo signaling pathway
9	Tight junction
10	Dopaminergic synapse
11	Long-term depression
12	Chagas disease (American trypanosomiasis)
13	Hepatitis C
Panther Pathway	[+] 6 Panther Pathways	+
1	EGF receptor signaling pathway
2	FGF signaling pathway
3	Wnt signaling pathway
4	p53 pathway
5	p53 pathway by glucose deprivation
6	p53 pathway feedback loops 2
PID Pathway	[+] 9 PID Pathways	+
1	ATR signaling pathway
2	PLK1 signaling events
3	C-MYC pathway
4	ErbB1 downstream signaling
5	PDGFR-beta signaling pathway
6	IL8- and CXCR2-mediated signaling events
7	p53 pathway
8	Regulation of retinoblastoma protein
9	TGF-beta receptor signaling
Reactome	[+] 21 Reactome Pathways	+
1	Spry regulation of FGF signaling
2	DARPP-32 events
3	Degradation of beta-catenin by the destruction complex
4	ERK/MAPK targets
5	MASTL Facilitates Mitotic Progression
6	Separation of Sister Chromatids
7	Resolution of Sister Chromatid Cohesion
8	CTLA4 inhibitory signaling
9	Platelet sensitization by LDL
10	Disassembly of the destruction complex and recruitment of AXIN to the membrane
11	S33 mutants of beta-catenin aren't phosphorylated
12	S37 mutants of beta-catenin aren't phosphorylated
13	S45 mutants of beta-catenin aren't phosphorylated
14	T41 mutants of beta-catenin aren't phosphorylated
15	RHO GTPases Activate Formins
16	RAF activation
17	Negative regulation of MAPK pathway
18	Mitotic Prometaphase
19	Cyclin D associated events in G1
20	Cyclin A/B1 associated events during G2/M transition
21	Glycolysis
WikiPathways	[+] 9 WikiPathways	+
1	Glycogen Metabolism
2	Wnt Signaling Pathway and Pluripotency
3	Mesodermal Commitment Pathway
4	Mitotic Metaphase and Anaphase
5	Nonsense-Mediated Decay
6	Dopamine metabolism
7	BDNF signaling pathway
8	TNF alpha Signaling Pathway
9	Signaling by FGFR

References

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REF 1

Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)

REF 2

ClinicalTrials.gov (NCT03377803) Cantharidin Application in Molluscum Patients (CAMP-2). U.S. National Institutes of Health.

REF 3

ClinicalTrials.gov (NCT03027388) Protein Phosphatase 2A Inhibitor, in Recurrent Glioblastoma. U.S. National Institutes of Health.

REF 4

Inhibition of protein phosphatase 2A enhances cytotoxicity and accessibility of chemotherapeutic drugs to hepatocellular carcinomas. Mol Cancer Ther. 2014 Aug;13(8):2062-72.

REF 5

Structure of protein phosphatase 2A core enzyme bound to tumor-inducing toxins. Cell. 2006 Oct 20;127(2):341-53.

REF 6

A structural basis for the reduced toxicity of dinophysistoxin-2. Chem Res Toxicol. 2009 Nov;22(11):1782-6.

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