Target Information
| Target General Information | Top | |||||
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| Target ID |
T36581
(Former ID: TTDI03387)
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| Target Name |
MAPK-activated protein kinase 3 (MAPKAPK3)
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| Synonyms |
MAPKAPK3
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| Gene Name |
MAPKAPK3
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| Target Type |
Literature-reported target
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[1] | ||||
| Function |
Stress-activated serine/threonine-protein kinase involved in cytokines production, endocytosis, cell migration, chromatin remodeling and transcriptional regulation. Following stress, it is phosphorylated and activated by MAP kinase p38-alpha/MAPK14, leading to phosphorylation of substrates. Phosphorylates serine in the peptide sequence, Hyd-X-R-X2-S, where Hyd is a large hydrophobic residue. MAPKAPK2 and MAPKAPK3, share the same function and substrate specificity, but MAPKAPK3 kinase activity and level in protein expression are lower compared to MAPKAPK2. Phosphorylates HSP27/HSPB1, KRT18, KRT20, RCSD1, RPS6KA3, TAB3 and TTP/ZFP36. Mediates phosphorylation of HSP27/HSPB1 in response to stress, leading to dissociate HSP27/HSPB1 from large small heat-shock protein (sHsps) oligomers and impair their chaperone activities and ability to protect against oxidative stress effectively. Involved in inflammatory response by regulating tumor necrosis factor (TNF) and IL6 production post-transcriptionally: acts by phosphorylating AU-rich elements (AREs)-binding proteins, such as TTP/ZFP36, leading to regulate the stability and translation of TNF and IL6 mRNAs. Phosphorylation of TTP/ZFP36, a major post-transcriptional regulator of TNF, promotes its binding to 14-3-3 proteins and reduces its ARE mRNA affinity leading to inhibition of dependent degradation of ARE-containing transcript. Involved in toll-like receptor signaling pathway (TLR) in dendritic cells: required for acute TLR-induced macropinocytosis by phosphorylating and activating RPS6KA3. Also acts as a modulator of Polycomb-mediated repression.
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| UniProt ID | ||||||
| EC Number |
EC 2.7.11.1
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| Sequence |
MDGETAEEQGGPVPPPVAPGGPGLGGAPGGRREPKKYAVTDDYQLSKQVLGLGVNGKVLE
CFHRRTGQKCALKLLYDSPKARQEVDHHWQASGGPHIVCILDVYENMHHGKRCLLIIMEC MEGGELFSRIQERGDQAFTEREAAEIMRDIGTAIQFLHSHNIAHRDVKPENLLYTSKEKD AVLKLTDFGFAKETTQNALQTPCYTPYYVAPEVLGPEKYDKSCDMWSLGVIMYILLCGFP PFYSNTGQAISPGMKRRIRLGQYGFPNPEWSEVSEDAKQLIRLLLKTDPTERLTITQFMN HPWINQSMVVPQTPLHTARVLQEDKDHWDEVKEEMTSALATMRVDYDQVKIKDLKTSNNR LLNKRRKKQAGSSSASQGCNNQ Click to Show/Hide
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| 3D Structure | Click to Show 3D Structure of This Target | PDB | ||||
| 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: PMID17480064C16 | Ligand Info | |||||
| Structure Description | High resolution crystal structure of mitogen-activated protein kinase-activated protein kinase 3 (MK3)-inhibitor complex | PDB:3FHR | ||||
| Method | X-ray diffraction | Resolution | 1.90 Å | Mutation | No | [2] |
| PDB Sequence |
EPKKYAVTDD
42 YQLSKQVLGL52 GVNGKVLECF62 HRRTGQKCAL72 KLLYDSPKAR82 QEVDHHWQAS 92 GGPHIVCILD102 VYENMHHGKR112 CLLIIMECME122 GGELFSRIQE132 RDQAFTEREA 143 AEIMRDIGTA153 IQFLHSHNIA163 HRDVKPENLL173 YTSKEKDAVL183 KLTDFGFAKE 193 TEKYDKSCDM225 WSLGVIMYIL235 LCGFPPFGFP266 NPEWSEVSED276 AKQLIRLLLK 286 TDPTERLTIT296 QFMNHPWINQ306 SMVVPQTPLH316 TARVLQEDKD326 HWDEVKEEMT 336 SALATMRVDY346 DQV
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LEU50
3.745
GLY51
4.130
LEU52
3.543
GLY53
3.380
VAL58
3.605
ALA71
3.356
LYS73
2.895
GLU84
4.584
VAL98
4.802
MET118
4.064
GLU119
3.250
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| Click to View More Binding Site Information of This Target and Ligand Pair | ||||||
| Ligand Name: 2-[2-(2-fluorophenyl)pyridin-4-yl]-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one | Ligand Info | |||||
| Structure Description | High resolution crystal structure of mitogen-activated protein kinase-activated protein kinase 3/inhibitor 2 complex | PDB:3FXW | ||||
| Method | X-ray diffraction | Resolution | 2.00 Å | Mutation | No | [3] |
| PDB Sequence |
EPKKYAVTDD
42 YQLSKQVLGL52 GVGKVLECFH63 RRTGQKCALK73 LLYDSPKARQ83 EVDHHWQASG 93 GPHIVCILDV103 YENMHHGKRC113 LLIIMECMEG123 GELFSRIQER133 DQAFTEREAA 144 EIMRDIGTAI154 QFLHSHNIAH164 RDVKPENLLY174 TSKEKDAVLK184 LTDFGFAKEE 217 KYDKSCDMWS227 LGVIMYILLC237 GFPPFGFPNP268 EWSEVSEDAK278 QLIRLLLKTD 288 PTERLTITQF298 MNHPWINQSM308 VVPQTPLHTA318 RVLQEDKDHW328 DEVKEEMTSA 338 LATMRVDYDQ348 V
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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 | ||
| VEGF signaling pathway | hsa04370 | Affiliated Target |
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| Class: Environmental Information Processing => Signal transduction | Pathway Hierarchy | ||
| Degree | 4 | Degree centrality | 4.30E-04 | Betweenness centrality | 3.86E-06 |
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| Closeness centrality | 2.12E-01 | Radiality | 1.37E+01 | Clustering coefficient | 3.33E-01 |
| Neighborhood connectivity | 2.40E+01 | Topological coefficient | 3.39E-01 | Eccentricity | 12 |
| 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 | ||||||
| References | Top | |||||
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| REF 1 | Pyrrolopyridine inhibitors of mitogen-activated protein kinase-activated protein kinase 2 (MK-2). J Med Chem. 2007 May 31;50(11):2647-54. | |||||
| REF 2 | High-resolution crystal structure of human Mapkap kinase 3 in complex with a high affinity ligand. Protein Sci. 2010 Jan;19(1):168-73. | |||||
| REF 3 | High resolution crystal structure of mitogen-activated protein kinase-activated protein kinase 3/inhibitor 2 complex | |||||
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