Target Information
| Target General Information | Top | |||||
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| Target ID |
T46685
(Former ID: TTDI00245)
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| Target Name |
CDC-like kinase 1 (CLK1)
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| Synonyms |
Dual specificity protein kinase CLK1; CLK; CDClike kinase 1
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| Gene Name |
CLK1
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| Target Type |
Patented-recorded target
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[1] | ||||
| Function |
Phosphorylates serine- and arginine-rich (SR) proteins of the spliceosomal complex and may be a constituent of a network of regulatory mechanisms that enable SR proteins to control RNA splicing. Phosphorylates: SRSF1, SRSF3 and PTPN1. Regulates the alternative splicing of tissue factor (F3) pre-mRNA in endothelial cells and adenovirus E1A pre-mRNA. Dual specificity kinase acting on both serine/threonine and tyrosine-containing substrates.
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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 |
MRHSKRTYCPDWDDKDWDYGKWRSSSSHKRRKRSHSSAQENKRCKYNHSKMCDSHYLESR
SINEKDYHSRRYIDEYRNDYTQGCEPGHRQRDHESRYQNHSSKSSGRSGRSSYKSKHRIH HSTSHRRSHGKSHRRKRTRSVEDDEEGHLICQSGDVLSARYEIVDTLGEGAFGKVVECID HKAGGRHVAVKIVKNVDRYCEAARSEIQVLEHLNTTDPNSTFRCVQMLEWFEHHGHICIV FELLGLSTYDFIKENGFLPFRLDHIRKMAYQICKSVNFLHSNKLTHTDLKPENILFVQSD YTEAYNPKIKRDERTLINPDIKVVDFGSATYDDEHHSTLVSTRHYRAPEVILALGWSQPC DVWSIGCILIEYYLGFTVFPTHDSKEHLAMMERILGPLPKHMIQKTRKRKYFHHDRLDWD EHSSAGRYVSRRCKPLKEFMLSQDVEHERLFDLIQKMLEYDPAKRITLREALKHPFFDLL KKSI 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: CX-4945 | Ligand Info | |||||
| Structure Description | Crystal structure of CLK1 in complex with CX-4945 | PDB:6KHD | ||||
| Method | X-ray diffraction | Resolution | 2.70 Å | Mutation | No | [5] |
| PDB Sequence |
LICQSGDVLS
158 ARYEIVDTLG168 EGAFGKVVEC178 IDHKAGGRHV188 AVKIVKNVDR198 YCEAARSEIQ 208 VLEHLNTTDP218 NSTFRCVQML228 EWFEHHGHIC238 IVFELLGLST248 YDFIKENGFL 258 PFRLDHIRKM268 AYQICKSVNF278 LHSNKLTHTD288 LKPENILFVQ298 SDYTEERTLI 317 NPDIKVVDFG327 SATYDDEHHS337 TLVRHYRAPE349 VILALGWSQP359 CDVWSIGCIL 369 IEYYLGFTVF379 PTHDSKEHLA389 MMERILGPLP399 KHMIQKTRKR409 KYFHHDRLDW 419 DEHSSAGRYV429 SRACKPLKEF439 MLSQDVEHER449 LFDLIQKMLE459 YDPAKRITLR 469 EALKHPFFDL479 LK
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LEU167
3.424
GLY168
3.483
GLU169
3.637
GLY170
4.199
PHE172
3.294
GLY173
4.516
LYS174
4.794
VAL175
3.623
ALA189
3.424
LYS191
2.679
GLU206
3.669
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| Ligand Name: DEBROMOHYMENIALDISINE | Ligand Info | |||||
| Structure Description | Crystal structure of human CLK1 in complex with 10Z-Hymenialdisine | PDB:1Z57 | ||||
| Method | X-ray diffraction | Resolution | 1.70 Å | Mutation | No | [6] |
| PDB Sequence |
SMHLICQSGD
155 VLSARYEIVD165 TLGEGAFGKV175 VECIDHKAGG185 RHVAVKIVKN195 VDRYCEAARS 205 EIQVLEHLNT215 TDPNSTFRCV225 QMLEWFEHHG235 HICIVFELLG245 LSTYDFIKEN 255 GFLPFRLDHI265 RKMAYQICKS275 VNFLHSNKLT285 HTDLKPENIL295 FVQSDYTEAY 305 NRDERTLINP319 DIKVVDFGSA329 TYDDEHHSTL339 VSTRHYRAPE349 VILALGWSQP 359 CDVWSIGCIL369 IEYYLGFTVF379 PTHDSKEHLA389 MMERILGPLP399 KHMIQKTRKR 409 KYFHHDRLDW419 DEHSSAGRYV429 SRACKPLKEF439 MLSQDVEHER449 LFDLIQKMLE 459 YDPAKRITLR469 EALKHPFFDL479 LKK
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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 | 1 | Degree centrality | 1.07E-04 | Betweenness centrality | 0.00E+00 |
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| Closeness centrality | 1.07E-04 | Radiality | 3.98E-03 | Clustering coefficient | 0.00E+00 |
| Neighborhood connectivity | 1.00E+00 | Topological coefficient | . | Eccentricity | 1 |
| 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 Affiliated Biological Pathways | Top | |||||
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| NetPath Pathway | [+] 3 NetPath Pathways | + | ||||
| 1 | TCR Signaling Pathway | |||||
| 2 | EGFR1 Signaling Pathway | |||||
| 3 | TGF_beta_Receptor Signaling Pathway | |||||
| WikiPathways | [+] 1 WikiPathways | + | ||||
| 1 | mRNA Processing | |||||
| References | Top | |||||
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| REF 1 | A systematic interaction map of validated kinase inhibitors with Ser/Thr kinases. Proc Natl Acad Sci U S A. 2007 Dec 18;104(51):20523-8. | |||||
| 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 | Structural Basis for the Selective Inhibition of Cdc2-Like Kinases by CX-4945. Biomed Res Int. 2019 Aug 18;2019:6125068. | |||||
| REF 6 | Kinase domain insertions define distinct roles of CLK kinases in SR protein phosphorylation. Structure. 2009 Mar 11;17(3):352-62. | |||||
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