Target Information
| Target General Information | Top | |||||
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| Target ID |
T00043
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| Target Name |
HUMAN cyclin G-associated kinase (GAK)
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| Synonyms |
cyclin G associated kinase
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| Gene Name |
GAK
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| Disease | [+] 1 Target-related Diseases | + | ||||
| 1 | Rheumatoid arthritis [ICD-11: FA20] | |||||
| Function |
Associates with cyclin G and CDK5. Seems to act as an auxilin homolog that is involved in the uncoating of clathrin-coated vesicles by Hsc70 in non-neuronal cells. Expression oscillates slightly during the cell cycle, peaking at G1.
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| BioChemical Class |
Ser/Thr protein kinase family
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| UniProt ID | ||||||
| EC Number |
EC 2.7.11.1
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| Sequence |
MSLLQSALDFLAGPGSLGGASGRDQSDFVGQTVELGELRLRVRRVLAEGGFAFVYEAQDV
GSGREYALKRLLSNEEEKNRAIIQEVCFMKKLSGHPNIVQFCSAASIGKEESDTGQAEFL LLTELCKGQLVEFLKKMESRGPLSCDTVLKIFYQTCRAVQHMHRQKPPIIHRDLKVENLL LSNQGTIKLCDFGSATTISHYPDYSWSAQRRALVEEEITRNTTPMYRTPEIIDLYSNFPI GEKQDIWALGCILYLLCFRQHPFEDGAKLRIVNGKYSIPPHDTQYTVFHSLIRAMLQVNP EERLSIAEVVHQLQEIAAARNVNPKSPITELLEQNGGYGSATLSRGPPPPVGPAGSGYSG GLALAEYDQPYGGFLDILRGGTERLFTNLKDTSSKVIQSVANYAKGDLDISYITSRIAVM SFPAEGVESALKNNIEDVRLFLDSKHPGHYAVYNLSPRTYRPSRFHNRVSECGWAARRAP HLHTLYNICRNMHAWLRQDHKNVCVVHCMDGRAASAVAVCSFLCFCRLFSTAEAAVYMFS MKRCPPGIWPSHKRYIEYMCDMVAEEPITPHSKPILVRAVVMTPVPLFSKQRSGCRPFCE VYVGDERVASTSQEYDKMRDFKIEDGKAVIPLGVTVQGDVLIVIYHARSTLGGRLQAKMA SMKMFQIQFHTGFVPRNATTVKFAKYDLDACDIQEKYPDLFQVNLEVEVEPRDRPSREAP PWENSSMRGLNPKILFSSREEQQDILSKFGKPELPRQPGSTAQYDAGAGSPEAEPTDSDS PPSSSADASRFLHTLDWQEEKEAETGAENASSKESESALMEDRDESEVSDEGGSPISSEG QEPRADPEPPGLAAGLVQQDLVFEVETPAVLPEPVPQEDGVDLLGLHSEVGAGPAVPPQA CKAPSSNTDLLSCLLGPPEAASQGPPEDLLSEDPLLLASPAPPLSVQSTPRGGPPAAADP FGPLLPSSGNNSQPCSNPDLFGEFLNSDSVTVPPSFPSAHSAPPPSCSADFLHLGDLPGE PSKMTASSSNPDLLGGWAAWTETAASAVAPTPATEGPLFSPGGQPAPCGSQASWTKSQNP DPFADLGDLSSGLQGSPAGFPPGGFIPKTATTPKGSSSWQTSRPPAQGASWPPQAKPPPK ACTQPRPNYASNFSVIGAREERGVRAPSFAQKPKVSENDFEDLLSNQGFSSRSDKKGPKT IAEMRKQDLAKDTDPLKLKLLDWIEGKERNIRALLSTLHTVLWDGESRWTPVGMADLVAP EQVKKHYRRAVLAVHPDKAAGQPYEQHAKMIFMELNDAWSEFENQGSRPLF Click to Show/Hide
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| 3D Structure | Click to Show 3D Structure of This Target | AlphaFold | ||||
| Drugs and Modes of Action | Top | |||||
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| Drugs in Phase 3 Trial | [+] 1 | + | ||||
| 1 | Baricitinib | Drug Info | Approved | Rheumatoid arthritis | [2] | |
| Mode of Action | [+] 1 Modes of Action | + | ||||
| Inhibitor | [+] 1 Inhibitor drugs | + | ||||
| 1 | Baricitinib | Drug Info | [1], [3] | |||
| 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: Gefitinib | Ligand Info | |||||
| Structure Description | Complex structure of cyclin G-associated kinase with gefitinib | PDB:5Y80 | ||||
| Method | X-ray diffraction | Resolution | 2.50 Å | Mutation | No | [4] |
| PDB Sequence |
SQSDFVGQTV
33 ELGELRLRVR43 RVLAEGGFAF53 VYEAQDVGSG63 REYALKRLLS73 NEEEKNRAII 83 QEVCFMKKLS93 GHPNIVQFCS103 AASIGKEESD113 TGQAEFLLLT123 ELCKGQLVEF 133 LKKMGPLSCD146 TVLKIFYQTC156 RAVQHMHRQK166 PPIIHRDLKV176 ENLLLSNQGT 186 IKLCDFGSAT196 TISHYPDYSW206 SAQRRALVEE216 EITRNTTPMY226 RTPEIIDLYS 236 NFPIGEKQDI246 WALGCILYLL256 CFRQHPFEDG266 AKLRIVNGKY276 SIPPHDTQYT 286 VFHSLIRAML296 QVNPEERLSI306 AEVVHQLQEI316 AAARNVNPKS326 PITELL |
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ARG44
4.748
LEU46
3.283
ALA47
4.210
VAL54
3.770
ALA67
3.600
LEU68
4.709
LYS69
3.329
GLU77
4.492
LYS78
4.324
ALA81
3.668
GLU85
3.480
VAL99
4.868
LEU121
4.040
THR123
3.994
GLU124
3.464
LEU125
3.700
CYS126
3.060
LYS127
3.393
GLY128
3.470
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| Click to View More Binding Site Information of This Target and Ligand Pair | ||||||
| Ligand Name: 2-Methoxy-4-[3-(Morpholin-4-Yl)[1,2]thiazolo[4,3-B]pyridin-6-Yl]aniline | Ligand Info | |||||
| Structure Description | Crystal structure of Cyclin-G associated kinase (GAK) complexed with selective 12i inhibitor | PDB:4Y8D | ||||
| Method | X-ray diffraction | Resolution | 2.10 Å | Mutation | No | [5] |
| PDB Sequence |
DFVGQTVELG
36 ELRLRVRRVL46 AEGGFAFVYE56 AQDVGSGREY66 ALKRLLSNEE76 EKNRAIIQEV 86 CFMKKLSGHP96 NIVQFCSAAS106 IGKEESDTGQ116 AEFLLLTELC126 KGQLVEFLKK 136 MESRGPLSCD146 TVLKIFYQTC156 RAVQHMHRQK166 PPIIHRDLKV176 ENLLLSNQGT 186 IKLCDFGSAT196 TISHYPYSNF238 PIGEKQDIWA248 LGCILYLLCF258 RQHPFSIPPH 281 DTQYTVFHSL291 IRAMLQVNPE301 ERLSIAEVVH311 QLQEIAAARN321 VNPKSPITEL 331 LE
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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 | 7 | Degree centrality | 7.52E-04 | Betweenness centrality | 4.71E-04 |
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| Closeness centrality | 2.17E-01 | Radiality | 1.38E+01 | Clustering coefficient | 9.52E-02 |
| Neighborhood connectivity | 1.91E+01 | Topological coefficient | 1.64E-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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| Co-Targets | Top | |||||
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| Co-Targets | ||||||
| References | Top | |||||
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| REF 1 | Baricitinib as potential treatment for 2019-nCoV acute respiratory disease. Lancet. 2020 Feb 15;395(10223):e30-e31. | |||||
| REF 2 | Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services. 2015 | |||||
| REF 3 | COVID-19: combining antiviral and anti-inflammatory treatments. Lancet Infect Dis. 2020 Apr;20(4):400-402. | |||||
| REF 4 | Structural Basis for the Inhibition of Cyclin G-Associated Kinase by Gefitinib. ChemistryOpen. 2018 Sep 10;7(9):721-727. | |||||
| REF 5 | Selective Inhibitors of Cyclin G Associated Kinase (GAK) as Anti-Hepatitis C Agents. J Med Chem. 2015 Apr 23;58(8):3393-410. | |||||
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