Target Information
Target General Information | Top | |||||
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Target ID |
T97149
(Former ID: TTDI03165)
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Target Name |
Dual-specificity tyrosine-phosphorylation regulated kinase 3 (DYRK3)
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Synonyms |
Regulatory erythroid kinase; REDK; Dual specificity tyrosine-phosphorylation-regulated kinase 3
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Gene Name |
DYRK3
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Target Type |
Patented-recorded target
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[1] | ||||
Function |
Dual-specificity tyrosine-regulated kinases (DYRKs) autophosphorylate a critical tyrosine residue in their activation loop and phosphorylate their substrate on serine and threonine residues. Acts as a central dissolvase of membraneless organelles during the G2-to-M transition, after the nuclear-envelope breakdown: acts by mediating phosphorylation of multiple serine and threonine residues in unstructured domains of proteins, such as SRRM1 and PCM1. Does not mediate disassembly of all membraneless organelles: disassembly of P-body and nucleolus is not regulated by DYRK3. Dissolution of membraneless organelles at the onset of mitosis is also required to release mitotic regulators, such as ZNF207, from liquid-unmixed organelles where they are sequestered and keep them dissolved during mitosis. Regulates mTORC1 by mediating the dissolution of stress granules: during stressful conditions, DYRK3 partitions from the cytosol to the stress granule, together with mTORC1 components, which prevents mTORC1 signaling. When stress signals are gone, the kinase activity of DYRK3 is required for the dissolution of stress granule and mTORC1 relocation to the cytosol: acts by mediating the phosphorylation of the mTORC1 inhibitor AKT1S1, allowing full reactivation of mTORC1 signaling. Also acts as a negative regulator of EPO-dependent erythropoiesis: may place an upper limit on red cell production during stress erythropoiesis. Inhibits cell death due to cytokine withdrawal in hematopoietic progenitor cells. Promotes cell survival upon genotoxic stress through phosphorylation of SIRT1: this in turn inhibits p53/TP53 activity and apoptosis. Dual-specificity protein kinase that promotes disassembly of several types of membraneless organelles during mitosis, such as stress granules, nuclear speckles and pericentriolar material.
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BioChemical Class |
Kinase
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UniProt ID | ||||||
EC Number |
EC 2.7.12.1
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Sequence |
MGGTARGPGRKDAGPPGAGLPPQQRRLGDGVYDTFMMIDETKCPPCSNVLCNPSEPPPPR
RLNMTTEQFTGDHTQHFLDGGEMKVEQLFQEFGNRKSNTIQSDGISDSEKCSPTVSQGKS SDCLNTVKSNSSSKAPKVVPLTPEQALKQYKHHLTAYEKLEIINYPEIYFVGPNAKKRHG VIGGPNNGGYDDADGAYIHVPRDHLAYRYEVLKIIGKGSFGQVARVYDHKLRQYVALKMV RNEKRFHRQAAEEIRILEHLKKQDKTGSMNVIHMLESFTFRNHVCMAFELLSIDLYELIK KNKFQGFSVQLVRKFAQSILQSLDALHKNKIIHCDLKPENILLKHHGRSSTKVIDFGSSC FEYQKLYTYIQSRFYRAPEIILGSRYSTPIDIWSFGCILAELLTGQPLFPGEDEGDQLAC MMELLGMPPPKLLEQSKRAKYFINSKGIPRYCSVTTQADGRVVLVGGRSRRGKKRGPPGS KDWGTALKGCDDYLFIEFLKRCLHWDPSARLTPAQALRHPWISKSVPRPLTTIDKVSGKR VVNPASAFQGLGSKLPPVVGIANKLKANLMSETNGSIPLCSVLPKLIS 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: Harmine | Ligand Info | |||||
Structure Description | Crystal structure of kinase | PDB:5Y86 | ||||
Method | X-ray diffraction | Resolution | 1.90 Å | Mutation | No | [3] |
PDB Sequence |
VVPLTPEQAL
147 KQYKHHLTAY157 EKLEIINYPE167 IYFVGPNAKK177 RHGVIGGPNN187 GGYDDADGAY 197 IHVPRDHLAY207 RYEVLKIIGK217 GSFGQVARVY227 DHKLRQYVAL237 KMVRNEKRFH 247 RQAAEEIRIL257 EHLKKQDKTG267 SMNVIHMLES277 FTFRNHVCMA287 FELLSIDLYE 297 LIKKNKFQGF307 SVQLVRKFAQ317 SILQSLDALH327 KNKIIHCDLK337 PENILLKHHG 347 RSTKVIDFGS358 SCFEYQKLYT368 IQSRFYRAPE379 IILGSRYSTP389 IDIWSFGCIL 399 AELLTGQPLF409 PGEDEGDQLA419 CMMELLGMPP429 PKLLEQSKRA439 KYFINKGIPR 450 YCSVTTQADG460 RVVLVGGRSR470 RGKKRGPPGS480 KDWGTALKGC490 DDYLFIEFLK 500 RCLHWDPSAR510 LPAQALRHPW521 ISKSVPRPLT531 T
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Ligand Name: L-serine-O-phosphate | Ligand Info | |||||
Structure Description | Crystal structure of kinase | PDB:5Y86 | ||||
Method | X-ray diffraction | Resolution | 1.90 Å | Mutation | No | [3] |
PDB Sequence |
VVPLTPEQAL
147 KQYKHHLTAY157 EKLEIINYPE167 IYFVGPNAKK177 RHGVIGGPNN187 GGYDDADGAY 197 IHVPRDHLAY207 RYEVLKIIGK217 GSFGQVARVY227 DHKLRQYVAL237 KMVRNEKRFH 247 RQAAEEIRIL257 EHLKKQDKTG267 SMNVIHMLES277 FTFRNHVCMA287 FELLSIDLYE 297 LIKKNKFQGF307 SVQLVRKFAQ317 SILQSLDALH327 KNKIIHCDLK337 PENILLKHHG 347 RSTKVIDFGS358 SCFEYQKLYT368 IQSRFYRAPE379 IILGSRYSTP389 IDIWSFGCIL 399 AELLTGQPLF409 PGEDEGDQLA419 CMMELLGMPP429 PKLLEQSKRA439 KYFINKGIPR 450 YCSVTTQADG460 RVVLVGGRSR470 RGKKRGPPGS480 KDWGTALKGC490 DDYLFIEFLK 500 RCLHWDPSAR510 LPAQALRHPW521 ISKSVPRPLT531 T
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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 Similarity Proteins
Human Tissue Distribution
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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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Chemical Structure based Activity Landscape of Target | Top |
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Drug Property Profile of Target | Top | |
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(1) Molecular Weight (mw) based Drug Clustering | (2) Octanol/Water Partition Coefficient (xlogp) based Drug Clustering | |
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(3) Hydrogen Bond Donor Count (hbonddonor) based Drug Clustering | (4) Hydrogen Bond Acceptor Count (hbondacc) based Drug Clustering | |
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(5) Rotatable Bond Count (rotbonds) based Drug Clustering | (6) Topological Polar Surface Area (polararea) based Drug Clustering | |
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"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 |
Target Poor or Non Binders | Top | |||||
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Target Poor or Non Binders |
References | Top | |||||
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REF 1 | Dual-specificity tyrosine phosphorylation-regulated kinase 1A (DYRK1A) inhibitors: a survey of recent patent literature.Expert Opin Ther Pat. 2017 Nov;27(11):1183-1199. | |||||
REF 2 | Structure and Property Based Design of Pyrazolo[1,5-a]pyrimidine Inhibitors of CK2 Kinase with Activity in Vivo. ACS Med Chem Lett. 2013 Jul 3;4(8):800-5. | |||||
REF 3 | Crystal Structure of Human Dual-Specificity Tyrosine-Regulated Kinase 3 Reveals New Structural Features and Insights into its Auto-phosphorylation. J Mol Biol. 2018 May 11;430(10):1521-1530. |
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