Target Information
| Target General Information | Top | |||||
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| Target ID |
T92803
(Former ID: TTDI03162)
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| Target Name |
Dual-specificity tyrosine-phosphorylation regulated kinase 1A (DYRK1A)
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| Synonyms |
hMNB; Protein kinase minibrain homolog; MNBH; MNB; HP86; Dual specificity tyrosine-phosphorylation-regulated kinase 1A; Dual specificity YAK1-related kinase; DYRK
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| Gene Name |
DYRK1A
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| Target Type |
Patented-recorded target
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[1] | ||||
| Disease | [+] 1 Target-related Diseases | + | ||||
| 1 | Cytomegaloviral disease [ICD-11: 1D82] | |||||
| Function |
Dual-specificity kinase which possesses both serine/threonine and tyrosine kinase activities. May play a role in a signaling pathway regulating nuclear functions of cell proliferation. Modulates alternative splicing by phosphorylating the splice factor SRSF6 (By similarity). Exhibits a substrate preference for proline at position P+1 and arginine at position P-3. Has pro-survival function and negatively regulates the apoptotic process. Promotes cell survival upon genotoxic stress through phosphorylation of SIRT1. This in turn inhibits TP53 activity and apoptosis (By similarity).
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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 |
MHTGGETSACKPSSVRLAPSFSFHAAGLQMAGQMPHSHQYSDRRQPNISDQQVSALSYSD
QIQQPLTNQVMPDIVMLQRRMPQTFRDPATAPLRKLSVDLIKTYKHINEVYYAKKKRRHQ QGQGDDSSHKKERKVYNDGYDDDNYDYIVKNGEKWMDRYEIDSLIGKGSFGQVVKAYDRV EQEWVAIKIIKNKKAFLNQAQIEVRLLELMNKHDTEMKYYIVHLKRHFMFRNHLCLVFEM LSYNLYDLLRNTNFRGVSLNLTRKFAQQMCTALLFLATPELSIIHCDLKPENILLCNPKR SAIKIVDFGSSCQLGQRIYQYIQSRFYRSPEVLLGMPYDLAIDMWSLGCILVEMHTGEPL FSGANEVDQMNKIVEVLGIPPAHILDQAPKARKFFEKLPDGTWNLKKTKDGKREYKPPGT RKLHNILGVETGGPGGRRAGESGHTVADYLKFKDLILRMLDYDPKTRIQPYYALQHSFFK KTADEGTNTSNSVSTSPAMEQSQSSGTTSSTSSSSGGSSGTSNSGRARSDPTHQHRHSGG HFTAAVQAMDCETHSPQVRQQFPAPLGWSGTEAPTQVTVETHPVQETTFHVAPQQNALHH HHGNSSHHHHHHHHHHHHHGQQALGNRTRPRVYNSPTNSSSTQDSMEVGHSHHSMTSLSS STTSSSTSSSSTGNQGNQAYQNRPVAANTLDFGQNGAMDVNLTVYSNPRQETGIAGHPTY QFSANTGPAHYMTEGHLTMRQGADREESPMTGVCVQQSPVASS Click to Show/Hide
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| 3D Structure | Click to Show 3D Structure of This Target | AlphaFold | ||||
| HIT2.0 ID | T39NFM | |||||
| 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: Midostaurin | Ligand Info | |||||
| Structure Description | Human DYRK1A in complex with PKC412 | PDB:4NCT | ||||
| Method | X-ray diffraction | Resolution | 2.60 Å | Mutation | No | [7] |
| PDB Sequence |
> Chain A
KVYNDGYDDD 143 NYDYIVKNGE153 KWMDRYEIDS163 LIGKGSFGQV173 VKAYDRVEQE183 WVAIKIIKNK 193 KAFLNQAQIE203 VRLLELMNKH213 DTEMKYYIVH223 LKRHFMFRNH233 LCLVFEMLSY 243 NLYDLLRNTN253 FRGVSLNLTR263 KFAQQMCTAL273 LFLATPELSI283 IHCDLKPENI 293 LLCNPKRSAI303 KIVDFGSSCQ313 LGQRIYQIQS324 RFYRSPEVLL334 GMPYDLAIDM 344 WSLGCILVEM354 HTGEPLFSGA364 NEVDQMNKIV374 EVLGIPPAHI384 LDQAPKARKF 394 FEKLPDGTWN404 LKKTEYKPPG419 TRKLHNILGV429 ETGGPGGRRA439 GESGHTVADY 449 LKFKDLILRM459 LDYDPKTRIQ469 PYYALQHSFF479 K> Chain C KVYNDGYDDD 143 NYDYIVKNGE153 KWMDRYEIDS163 LIGKGSFGQV173 VKAYDRVEQE183 WVAIKIIKNK 193 KAFLNQAQIE203 VRLLELMNKH213 DTEMKYYIVH223 LKRHFMFRNH233 LCLVFEMLSY 243 NLYDLLRNTN253 FRGVSLNLTR263 KFAQQMCTAL273 LFLATPELSI283 IHCDLKPENI 293 LLCNPKRAIK304 IVDFGSSCQL314 GQRIYQIQSR325 FYRSPEVLLG335 MPYDLAIDMW 345 SLGCILVEMH355 TGEPLFSGAN365 EVDQMNKIVE375 VLGIPPAHIL385 DQAPKARKFF 395 EKLPDGTWNL405 KKREYKPPGT420 RKLHNILGVE430 TGGPGGRRAG440 ESGHTVADYL 450 KFKDLILRML460 DYDPKTRIQP470 YYALQHSFF
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ILE165[A]
3.377
GLY166[A]
3.197
LYS167[A]
3.994
PHE170[A]
3.910
VAL173[A]
3.659
ALA186[A]
3.593
LYS188[A]
3.753
GLU203[A]
4.358
VAL222[A]
4.342
PHE238[A]
4.007
GLU239[A]
3.209
MET240[A]
3.545
LEU241[A]
2.988
SER242[A]
4.279
ASN244[A]
3.428
TYR246[A]
4.208
ARG250[A]
4.587
GLU291[A]
3.107
ASN292[A]
4.237
LEU294[A]
3.791
VAL306[A]
3.588
ASP307[A]
3.621
ILE165[C]
3.398
GLY166[C]
3.404
LYS167[C]
3.897
PHE170[C]
3.747
VAL173[C]
3.693
ALA186[C]
3.409
LYS188[C]
3.546
GLU203[C]
4.252
VAL222[C]
4.269
PHE238[C]
3.779
GLU239[C]
3.157
MET240[C]
3.509
LEU241[C]
3.147
SER242[C]
3.881
ASN244[C]
3.468
LYS289[C]
4.458
GLU291[C]
3.131
ASN292[C]
3.574
LEU294[C]
3.933
VAL306[C]
3.471
ASP307[C]
3.695
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| Ligand Name: Abemaciclib | Ligand Info | |||||
| Structure Description | Crystal structure of the human DYRK1A kinase domain bound to abemaciclib | PDB:7O7K | ||||
| Method | X-ray diffraction | Resolution | 1.82 Å | Mutation | No | [8] |
| PDB Sequence |
KVYNDGYDDD
143 NYDYIVKNGE153 KWMDRYEIDS163 LIGKGSFGQV173 VKAYDRVEQE183 WVAIKIIKNK 193 KAFLNQAQIE203 VRLLELMNKH213 DTEMKYYIVH223 LKRHFMFRNH233 LCLVFEMLSY 243 NLYDLLRNTN253 FRGVSLNLTR263 KFAQQMCTAL273 LFLATPELSI283 IHCDLKPENI 293 LLCNPKRSAI303 KIVDFGSSCQ313 LGQRIYQIQS324 RFYRSPEVLL334 GMPYDLAIDM 344 WSLGCILVEM354 HTGEPLFSGA364 NEVDQMNKIV374 EVLGIPPAHI384 LDQAPKARKF 394 FEKLPDGTWN404 LKKTKDREYK416 PPGTRKLHNI426 LGVETGGPGG436 RRAGESGHTV 446 ADYLKFKDLI456 LRMLDYDPKT466 RIQPYYALQH476 SFFK
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ILE165
2.971
GLY166
4.297
PHE170
3.600
VAL173
4.046
ALA186
3.543
LYS188
2.870
GLU203
3.590
VAL222
3.454
PHE238
3.123
GLU239
3.003
MET240
3.872
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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).
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
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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| Degree | 3 | Degree centrality | 3.22E-04 | Betweenness centrality | 2.99E-06 |
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| Closeness centrality | 1.67E-01 | Radiality | 1.26E+01 | Clustering coefficient | 3.33E-01 |
| Neighborhood connectivity | 7.33E+00 | Topological coefficient | 5.38E-01 | Eccentricity | 13 |
| Download | Click to Download the Full PPI Network of This Target | ||||
| 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 | ||||||
| Target Regulators | Top | |||||
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| Target-regulating microRNAs | ||||||
| Target-interacting Proteins | ||||||
| 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 | Specific CLK inhibitors from a novel chemotype for regulation of alternative splicing. Chem Biol. 2011 Jan 28;18(1):67-76. | |||||
| REF 3 | Leucettines, a class of potent inhibitors of cdc2-like kinases and dual specificity, tyrosine phosphorylation regulated kinases derived from the marine sponge leucettamine B: modulation of alternative pre-RNA splicing. J Med Chem. 2011 Jun 23;54(12):4172-86. | |||||
| REF 4 | Small-molecule pyrimidine inhibitors of the cdc2-like (Clk) and dual specificity tyrosine phosphorylation-regulated (Dyrk) kinases: development of chemical probe ML315. Bioorg Med Chem Lett. 2013 Jun15;23(12):3654-61. | |||||
| REF 5 | Tricyclic Pyrimidines As Inhibitors of DYRK1A/DYRK1B As Potential Treatment for Down's Syndrome or Alzheimer's Disease. ACS Med Chem Lett. 2013 Apr 26;4(6):502-3. | |||||
| REF 6 | 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. (Target id: 2009). | |||||
| REF 7 | The structure of a dual-specificity tyrosine phosphorylation-regulated kinase 1A-PKC412 complex reveals disulfide-bridge formation with the anomalous catalytic loop HRD(HCD) cysteine. Acta Crystallogr D Biol Crystallogr. 2015 May;71(Pt 5):1207-15. | |||||
| REF 8 | Abemaciclib is a potent inhibitor of DYRK1A and HIP kinases involved in transcriptional regulation. Nat Commun. 2021 Nov 16;12(1):6607. | |||||
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