Target Information

Target General Information

Target ID

T25464 (Former ID: TTDS00363)

Target Name

Calcineurin (PPP3CA)

Synonyms

Serine/threonine-protein phosphatase 2B catalytic subunit alpha isoform; Calmodulin-dependent calcineurin A subunit alpha isoform; CNA; CAM-PRP catalytic subunit; CALNA

Click to Show/Hide

Gene Name

PPP3CA

Target Type

Successful target

[1]

Disease

[+] 4 Target-related Diseases

Atopic eczema [ICD-11: EA80]

Lupus erythematosus [ICD-11: 4A40]

Psoriasis [ICD-11: EA90]

Transplant rejection [ICD-11: NE84]

Function

Many of the substrates contain a PxIxIT motif and/or a LxVP motif. In response to increased Ca(2+) levels, dephosphorylates and activates phosphatase SSH1 which results in cofilin dephosphorylation. In response to increased Ca(2+) levels following mitochondrial depolarization, dephosphorylates DNM1L inducing DNM1L translocation to the mitochondrion. Dephosphorylates heat shock protein HSPB1. Dephosphorylates and activates transcription factor NFATC1. In response to increased Ca(2+) levels, regulates NFAT-mediated transcription probably by dephosphorylating NFAT and promoting its nuclear translocation. Dephosphorylates and inactivates transcription factor ELK1. Dephosphorylates DARPP32. May dephosphorylate CRTC2 at 'Ser-171' resulting in CRTC2 dissociation from 14-3-3 proteins. Calcium-dependent, calmodulin-stimulated protein phosphatase which plays an essential role in the transduction of intracellular Ca(2+)-mediated signals.

Click to Show/Hide

BioChemical Class

Phosphoric monoester hydrolase

UniProt ID

PP2BA_HUMAN

EC Number

EC 3.1.3.16

Sequence

MSEPKAIDPKLSTTDRVVKAVPFPPSHRLTAKEVFDNDGKPRVDILKAHLMKEGRLEESV
ALRIITEGASILRQEKNLLDIDAPVTVCGDIHGQFFDLMKLFEVGGSPANTRYLFLGDYV
DRGYFSIECVLYLWALKILYPKTLFLLRGNHECRHLTEYFTFKQECKIKYSERVYDACMD
AFDCLPLAALMNQQFLCVHGGLSPEINTLDDIRKLDRFKEPPAYGPMCDILWSDPLEDFG
NEKTQEHFTHNTVRGCSYFYSYPAVCEFLQHNNLLSILRAHEAQDAGYRMYRKSQTTGFP
SLITIFSAPNYLDVYNNKAAVLKYENNVMNIRQFNCSPHPYWLPNFMDVFTWSLPFVGEK
VTEMLVNVLNICSDDELGSEEDGFDGATAAARKEVIRNKIRAIGKMARVFSVLREESESV
LTLKGLTPTGMLPSGVLSGGKQTLQSATVEAIEADEAIKGFSPQHKITSFEEAKGLDRIN
ERMPPRRDAMPSDANLNSINKALTSETNGTDSNGSNSSNIQ

Click to Show/Hide

3D Structure

Click to Show 3D Structure of This Target

PDB

HIT2.0 ID

T71DUF

Drugs and Modes of Action

Top

Approved Drug(s)

[+] 4 Approved Drugs

Ciclosporin

Drug Info

Approved

Psoriasis vulgaris

[1]

Pimecrolimus

Drug Info

Approved

Atopic dermatitis

[2], [3]

Tacrolimus

Drug Info

Approved

Organ transplant rejection

[4], [5]

Voclosporin

Drug Info

Approved

Lupus nephritis

[6]

Mode of Action

[+] 1 Modes of Action

Inhibitor

[+] 5 Inhibitor drugs

Ciclosporin

Drug Info

[1]

Pimecrolimus

Drug Info

[7]

Tacrolimus

Drug Info

[8]

Voclosporin

Drug Info

[6]

L-685,818

Drug Info

[9]

Cell-based Target Expression Variations

Top

Cell-based Target Expression Variations

Cell-based Target Expression Variations Info

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

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

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
MAPK signaling pathway	hsa04010	Affiliated Target
Class: Environmental Information Processing => Signal transduction	Pathway Hierarchy
Calcium signaling pathway	hsa04020	Affiliated Target
Class: Environmental Information Processing => Signal transduction	Pathway Hierarchy
cGMP-PKG signaling pathway	hsa04022	Affiliated Target
Class: Environmental Information Processing => Signal transduction	Pathway Hierarchy
Oocyte meiosis	hsa04114	Affiliated Target
Class: Cellular Processes => Cell growth and death	Pathway Hierarchy
Cellular senescence	hsa04218	Affiliated Target
Class: Cellular Processes => Cell growth and death	Pathway Hierarchy
Wnt signaling pathway	hsa04310	Affiliated Target
Class: Environmental Information Processing => Signal transduction	Pathway Hierarchy
Axon guidance	hsa04360	Affiliated Target
Class: Organismal Systems => Development and regeneration	Pathway Hierarchy
VEGF signaling pathway	hsa04370	Affiliated Target
Class: Environmental Information Processing => Signal transduction	Pathway Hierarchy
Osteoclast differentiation	hsa04380	Affiliated Target
Class: Organismal Systems => Development and regeneration	Pathway Hierarchy
C-type lectin receptor signaling pathway	hsa04625	Affiliated Target
Class: Organismal Systems => Immune system	Pathway Hierarchy
Natural killer cell mediated cytotoxicity	hsa04650	Affiliated Target
Class: Organismal Systems => Immune system	Pathway Hierarchy
Th1 and Th2 cell differentiation	hsa04658	Affiliated Target
Class: Organismal Systems => Immune system	Pathway Hierarchy
Th17 cell differentiation	hsa04659	Affiliated Target
Class: Organismal Systems => Immune system	Pathway Hierarchy
T cell receptor signaling pathway	hsa04660	Affiliated Target
Class: Organismal Systems => Immune system	Pathway Hierarchy
B cell receptor signaling pathway	hsa04662	Affiliated Target
Class: Organismal Systems => Immune system	Pathway Hierarchy
Long-term potentiation	hsa04720	Affiliated Target
Class: Organismal Systems => Nervous system	Pathway Hierarchy
Glutamatergic synapse	hsa04724	Affiliated Target
Class: Organismal Systems => Nervous system	Pathway Hierarchy
Dopaminergic synapse	hsa04728	Affiliated Target
Class: Organismal Systems => Nervous system	Pathway Hierarchy
Oxytocin signaling pathway	hsa04921	Affiliated Target
Class: Organismal Systems => Endocrine system	Pathway Hierarchy
Glucagon signaling pathway	hsa04922	Affiliated Target
Class: Organismal Systems => Endocrine system	Pathway Hierarchy
Renin secretion	hsa04924	Affiliated Target
Class: Organismal Systems => Endocrine system	Pathway Hierarchy
Click to Show/Hide the Information of Affiliated Human Pathways

Degree	10	Degree centrality	1.07E-03	Betweenness centrality	6.01E-04
Closeness centrality	2.06E-01	Radiality	1.36E+01	Clustering coefficient	8.89E-02
Neighborhood connectivity	8.60E+00	Topological coefficient	1.22E-01	Eccentricity	12
Download	Click to Download the Full PPI Network of This Target

Chemical Structure based Activity Landscape of Target

Top

Drug Property Profile of Target

Top

(1) Molecular Weight (mw) based Drug Clustering

(2) Octanol/Water Partition Coefficient (xlogp) based Drug Clustering

(3) Hydrogen Bond Donor Count (hbonddonor) based Drug Clustering

(4) Hydrogen Bond Acceptor Count (hbondacc) based Drug Clustering

(5) Rotatable Bond Count (rotbonds) based Drug Clustering

(6) Topological Polar Surface Area (polararea) based Drug Clustering

"RO5" indicates the cutoff set by lipinski's rule of five; "D123AB" colored in GREEN denotes the no violation of any cutoff in lipinski's rule of five; "D123AB" colored in PURPLE refers to the violation of only one cutoff in lipinski's rule of five; "D123AB" colored in BLACK represents the violation of more than one cutoffs in lipinski's rule of five

Co-Targets

Top

Co-Targets

Co-Targets Info

Target Poor or Non Binders

Top

Target Poor or Non Binders

Target Poor or Non Binders Info

Target Regulators

Top

Target-regulating microRNAs

Target-regulating microRNAs Info

Target-interacting Proteins

Target-interacting Proteins Info

Target Profiles in Patients

Top

Target Expression
Profile (TEP)

Target Expression Profile Info

Target Affiliated Biological Pathways		Top
KEGG Pathway	[+] 22 KEGG Pathways	+
1	MAPK signaling pathway
2	Calcium signaling pathway
3	cGMP-PKG signaling pathway
4	Oocyte meiosis
5	Apoptosis
6	Wnt signaling pathway
7	Axon guidance
8	VEGF signaling pathway
9	Osteoclast differentiation
10	Natural killer cell mediated cytotoxicity
11	T cell receptor signaling pathway
12	B cell receptor signaling pathway
13	Long-term potentiation
14	Glutamatergic synapse
15	Dopaminergic synapse
16	Oxytocin signaling pathway
17	Glucagon signaling pathway
18	Alzheimer's disease
19	Amyotrophic lateral sclerosis (ALS)
20	Amphetamine addiction
21	Tuberculosis
22	HTLV-I infection
Reactome	[+] 3 Reactome Pathways	+
1	DARPP-32 events
2	FCERI mediated Ca+2 mobilization
3	Ca2+ pathway
WikiPathways	[+] 15 WikiPathways	+
1	Mitochondrial Gene Expression
2	MAPK Signaling Pathway
3	G Protein Signaling Pathways
4	Cardiac Hypertrophic Response
5	Fc epsilon receptor (FCERI) signaling
6	Signaling by the B Cell Receptor (BCR)
7	T-Cell Receptor and Co-stimulatory Signaling
8	Amyotrophic lateral sclerosis (ALS)
9	Spinal Cord Injury
10	Alzheimers Disease
11	miR-targeted genes in muscle cell - TarBase
12	miR-targeted genes in lymphocytes - TarBase
13	Opioid Signalling
14	MicroRNAs in cardiomyocyte hypertrophy
15	Physiological and Pathological Hypertrophy of the Heart

Target-Related Models and Studies

Top

Target Validation

Target Validation Info

References

Top

REF 1

Cyclosporine and tacrolimus for the treatment of rheumatoid arthritis. Curr Opin Rheumatol. 2007 May;19(3):238-45.

REF 2

URL: http://www.guidetopharmacology.org Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Ligand id: 6783).

REF 3

Emerging drugs for moderate-to-severe psoriasis. Expert Opin Emerg Drugs. 2005 Feb;10(1):35-52.

REF 4

REF 5

New developments in immunosuppressive therapy for heart transplantation. Expert Opin Emerg Drugs. 2009 Mar;14(1):1-21.

REF 6

Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health Human Services. 2021

REF 7

Treatment of chronic blepharokeratoconjunctivitis with local calcineurin inhibitors. Ophthalmologe. 2009 Jul;106(7):635-8.

REF 8

Emerging drugs for ocular allergy. Expert Opin Emerg Drugs. 2005 Aug;10(3):505-20.

REF 9

Synergistic antifungal activities of bafilomycin A(1), fluconazole, and the pneumocandin MK-0991/caspofungin acetate (L-743,873) with calcineurin inhibitors FK506 and L-685,818 against Cryptococcus neoformans. Antimicrob Agents Chemother. 2000 Mar;44(3):739-46.

If You Find Any Error in Data or Bug in Web Service, Please Kindly Report It to Dr. Zhou and Dr. Zhang.

Prof. Feng ZHU

Prof. Yuzong CHEN