Target Information
| Target General Information | Top | |||||
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| Target ID |
T04123
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| Target Name |
Serine/threonine-protein phosphatase 5 (PPP5C)
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| Synonyms |
Protein phosphatase T; PPT protein; PPP5; PP5; PP-T
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| Gene Name |
PPP5C
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| Target Type |
Patented-recorded target
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[1] | ||||
| Function |
Implicated in wide ranging cellular processes, including apoptosis, differentiation, DNA damage response, cell survival, regulation of ion channels or circadian rhythms, in response to steroid and thyroid hormones, calcium, fatty acids, TGF-beta as well as oxidative and genotoxic stresses. Participates in the control of DNA damage response mechanisms such as checkpoint activation and DNA damage repair through, for instance, the regulation ATM/ATR-signaling and dephosphorylation of PRKDC and TP53BP1. Inhibits ASK1/MAP3K5-mediated apoptosis induced by oxidative stress. Plays a positive role in adipogenesis, mainly through the dephosphorylation and activation of PPARG transactivation function. Also dephosphorylates and inhibits the anti-adipogenic effect of NR3C1. Regulates the circadian rhythms, through the dephosphorylation and activation of CSNK1E. May modulate TGF-beta signaling pathway by the regulation of SMAD3 phosphorylation and protein expression levels. Dephosphorylates and may play a role in the regulation of TAU/MAPT. Through their dephosphorylation, may play a role in the regulation of ions channels such as KCNH2. Serine/threonine-protein phosphatase that dephosphorylates a myriad of proteins involved in different signaling pathways including the kinases CSNK1E, ASK1/MAP3K5, PRKDC and RAF1, the nuclear receptors NR3C1, PPARG, ESR1 and ESR2, SMAD proteins and TAU/MAPT.
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| BioChemical Class |
Phosphoric monoester hydrolase
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| UniProt ID | ||||||
| EC Number |
EC 3.1.3.16
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| Sequence |
MAMAEGERTECAEPPRDEPPADGALKRAEELKTQANDYFKAKDYENAIKFYSQAIELNPS
NAIYYGNRSLAYLRTECYGYALGDATRAIELDKKYIKGYYRRAASNMALGKFRAALRDYE TVVKVKPHDKDAKMKYQECNKIVKQKAFERAIAGDEHKRSVVDSLDIESMTIEDEYSGPK LEDGKVTISFMKELMQWYKDQKKLHRKCAYQILVQVKEVLSKLSTLVETTLKETEKITVC GDTHGQFYDLLNIFELNGLPSETNPYIFNGDFVDRGSFSVEVILTLFGFKLLYPDHFHLL RGNHETDNMNQIYGFEGEVKAKYTAQMYELFSEVFEWLPLAQCINGKVLIMHGGLFSEDG VTLDDIRKIERNRQPPDSGPMCDLLWSDPQPQNGRSISKRGVSCQFGPDVTKAFLEENNL DYIIRSHEVKAEGYEVAHGGRCVTVFSAPNYCDQMGNKASYIHLQGSDLRPQFHQFTAVP HPNVKPMAYANTLLQLGMM Click to Show/Hide
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| 3D Structure | Click to Show 3D Structure of This Target | PDB | ||||
| HIT2.0 ID | T32P8F | |||||
| Cell-based Target Expression Variations | Top | |||||
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| Cell-based Target Expression Variations | ||||||
| Drug Binding Sites of Target | Top | |||||
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| Ligand Name: Cobalt Hexammine Ion | Ligand Info | |||||
| Structure Description | Phosphatase domain of PP5 bound to a phosphomimetic Cdc37 substrate peptide | PDB:5HPE | ||||
| Method | X-ray diffraction | Resolution | 2.27 Å | Mutation | Yes | [2] |
| PDB Sequence |
EYSGPKLEDG
184 KVTISFMKEL194 MQWYKDQKKL204 HRKCAYQILV214 QVKEVLSKLS224 TLVETTLKET 234 EKITVCGDTH244 GQFYDLLNIF254 ELNGLPSETN264 PYIFNGDFVD274 RGSFSVEVIL 284 TLFGFKLLYP294 DHFHLLRGNH304 ETDNMNQIYG314 FEGEVKAKYT324 AQMYELFSEV 334 FEWLPLAQCI344 NGKVLIMHGG354 LFSEDGVTLD364 DIRKIERNRQ374 PPDSGPMCDL 384 LWSDPQPQNG394 RSISKRGVSC404 QFGPDVTKAF414 LEENNLDYII424 RSHEVKAEGY 434 EVAHGGRCVT444 VFSAPNYCDQ454 MGNKASYIHL464 QGSDLRPQFH474 QFTAVPHPNV 484 KPMAYAWDHI1010 EVEDDE
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| Ligand Name: (1s,2r,3s,4r,5s)-5-Methyl-7-Oxabicyclo[2.2.1]heptane-2,3-Dicarboxylic Acid | Ligand Info | |||||
| Structure Description | Co-crystal structures of PP5 in complex with 5-methyl-7-oxabicyclo[2.2.1]heptane-2,3-dicarboxylic acid | PDB:4ZX2 | ||||
| Method | X-ray diffraction | Resolution | 1.23 Å | Mutation | No | [3] |
| PDB Sequence |
GASMTIEDEY
176 SGPKLEDGKV186 TISFMKELMQ196 WYKDQKKLHR206 KCAYQILVQV216 KEVLSKLSTL 226 VETTLKETEK236 ITVCGDTHGQ246 FYDLLNIFEL256 NGLPSETNPY266 IFNGDFVDRG 276 SFSVEVILTL286 FGFKLLYPDH296 FHLLRGNHET306 DNMNQIYGFE316 GEVKAKYTAQ 326 MYELFSEVFE336 WLPLAQCING346 KVLIMHGGLF356 SEDGVTLDDI366 RKIERNRQPP 376 DSGPMCDLLW386 SDPQPQNGRS396 ISKRGVSCQF406 GPDVTKAFLE416 ENNLDYIIRS 426 HEVKAEGYEV436 AHGGRCVTVF446 SAPNYCDQMG456 NKASYIHLQG466 SDLRPQFHQF 476 TAVPHPNVKP486 MAYAN
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| Click to View More Binding Site Information of This Target with Different Ligands | ||||||
| Different Human System Profiles of Target | Top |
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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
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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.
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| KEGG Pathway | Pathway ID | Affiliated Target | Pathway Map |
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| MAPK signaling pathway | hsa04010 | Affiliated Target |
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| Class: Environmental Information Processing => Signal transduction | Pathway Hierarchy | ||
| Degree | 7 | Degree centrality | 7.52E-04 | Betweenness centrality | 1.13E-05 |
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| Closeness centrality | 2.29E-01 | Radiality | 1.40E+01 | Clustering coefficient | 6.67E-01 |
| Neighborhood connectivity | 4.21E+01 | Topological coefficient | 2.09E-01 | Eccentricity | 11 |
| Download | Click to Download the Full PPI Network of This Target | ||||
| Chemical Structure based Activity Landscape of Target | Top |
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| Target Poor or Non Binders | Top | |||||
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| Target Poor or Non Binders | ||||||
| Target Regulators | Top | |||||
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| Target-interacting Proteins | ||||||
| Target Affiliated Biological Pathways | Top | |||||
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| KEGG Pathway | [+] 1 KEGG Pathways | + | ||||
| 1 | MAPK signaling pathway | |||||
| References | Top | |||||
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| REF 1 | Ligands for Ser/Thr phosphoprotein phosphatases: a patent review (2005-2015).Expert Opin Ther Pat. 2016;26(3):389-407. | |||||
| REF 2 | Structural and functional basis of protein phosphatase 5 substrate specificity. Proc Natl Acad Sci U S A. 2016 Aug 9;113(32):9009-14. | |||||
| REF 3 | Crystal structures and mutagenesis of PPP-family ser/thr protein phosphatases elucidate the selectivity of cantharidin and novel norcantharidin-based inhibitors of PP5C. Biochem Pharmacol. 2016 Jun 1;109:14-26. | |||||
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