Target Information
| Target General Information | Top | |||||
|---|---|---|---|---|---|---|
| Target ID |
T86437
|
|||||
| Target Name |
HUMAN janus kinase 1 (JAK-1)
|
|||||
| Synonyms |
Tyrosine-protein kinase JAK1; JAK1B; JAK1A
Click to Show/Hide
|
|||||
| Gene Name |
JAK1
|
|||||
| Disease | [+] 1 Target-related Diseases | + | ||||
| 1 | Myelofibrosis [ICD-11: 2A22] | |||||
| Function |
Kinase partner for the interleukin (IL)-2 receptor as well as interleukin (IL)-10 receptor. Tyrosine kinase of the non-receptor type, involved in the IFN-alpha/beta/gamma signal pathway.
Click to Show/Hide
|
|||||
| BioChemical Class |
Kinase
|
|||||
| UniProt ID | ||||||
| EC Number |
EC 2.7.10.2
|
|||||
| Sequence |
MQYLNIKEDCNAMAFCAKMRSSKKTEVNLEAPEPGVEVIFYLSDREPLRLGSGEYTAEEL
CIRAAQACRISPLCHNLFALYDENTKLWYAPNRTITVDDKMSLRLHYRMRFYFTNWHGTN DNEQSVWRHSPKKQKNGYEKKKIPDATPLLDASSLEYLFAQGQYDLVKCLAPIRDPKTEQ DGHDIENECLGMAVLAISHYAMMKKMQLPELPKDISYKRYIPETLNKSIRQRNLLTRMRI NNVFKDFLKEFNNKTICDSSVSTHDLKVKYLATLETLTKHYGAEIFETSMLLISSENEMN WFHSNDGGNVLYYEVMVTGNLGIQWRHKPNVVSVEKEKNKLKRKKLENKHKKDEEKNKIR EEWNNFSYFPEITHIVIKESVVSINKQDNKKMELKLSSHEEALSFVSLVDGYFRLTADAH HYLCTDVAPPLIVHNIQNGCHGPICTEYAINKLRQEGSEEGMYVLRWSCTDFDNILMTVT CFEKSEQVQGAQKQFKNFQIEVQKGRYSLHGSDRSFPSLGDLMSHLKKQILRTDNISFML KRCCQPKPREISNLLVATKKAQEWQPVYPMSQLSFDRILKKDLVQGEHLGRGTRTHIYSG TLMDYKDDEGTSEEKKIKVILKVLDPSHRDISLAFFEAASMMRQVSHKHIVYLYGVCVRD VENIMVEEFVEGGPLDLFMHRKSDVLTTPWKFKVAKQLASALSYLEDKDLVHGNVCTKNL LLAREGIDSECGPFIKLSDPGIPITVLSRQECIERIPWIAPECVEDSKNLSVAADKWSFG TTLWEICYNGEIPLKDKTLIEKERFYESRCRPVTPSCKELADLMTRCMNYDPNQRPFFRA IMRDINKLEEQNPDIVSEKKPATEVDPTHFEKRFLKRIRDLGEGHFGKVELCRYDPEGDN TGEQVAVKSLKPESGGNHIADLKKEIEILRNLYHENIVKYKGICTEDGGNGIKLIMEFLP SGSLKEYLPKNKNKINLKQQLKYAVQICKGMDYLGSRQYVHRDLAARNVLVESEHQVKIG DFGLTKAIETDKEYYTVKDDRDSPVFWYAPECLMQSKFYIASDVWSFGVTLHELLTYCDS DSSPMALFLKMIGPTHGQMTVTRLVNTLKEGKRLPCPPNCPDEVYQLMRKCWEFQPSNRT SFQNLIEGFEALLK Click to Show/Hide
|
|||||
| 3D Structure | Click to Show 3D Structure of This Target | AlphaFold | ||||
| Drugs and Modes of Action | Top | |||||
|---|---|---|---|---|---|---|
| Drugs in Phase 3 Trial | [+] 1 | + | ||||
| 1 | Ruxolitinib | Drug Info | Approved | Myelofibrosis | [2] | |
| Mode of Action | [+] 1 Modes of Action | + | ||||
| Inhibitor | [+] 1 Inhibitor drugs | + | ||||
| 1 | Ruxolitinib | Drug Info | [1], [3] | |||
| Cell-based Target Expression Variations | Top | |||||
|---|---|---|---|---|---|---|
| Cell-based Target Expression Variations | ||||||
| Drug Binding Sites of Target | Top | |||||
|---|---|---|---|---|---|---|
| Ligand Name: Tofacitinib | Ligand Info | |||||
| Structure Description | Crystal structures of JAK1 and JAK2 inhibitor complexes | PDB:3EYG | ||||
| Method | X-ray diffraction | Resolution | 1.90 Å | Mutation | No | [4] |
| PDB Sequence |
VDPTHFEKRF
874 LKRIRDLGEG884 HFGKVELCRY894 DPEGDNTGEQ904 VAVKSLKPHI919 ADLKKEIEIL 929 RNLYHENIVK939 YKGICTENGI952 KLIMEFLPSG962 SLKEYLPKNK972 NKINLKQQLK 982 YAVQICKGMD992 YLGSRQYVHR1002 DLAARNVLVE1012 SEHQVKIGDF1022 GLTKAIETDK 1032 ETVKDDRDSP1044 VFWYAPECLM1054 QSKFYIASDV1064 WSFGVTLHEL1074 LTYCDSDSSP 1084 MALFLKMIGP1094 THGQMTVTRL1104 VNTLKEGKRL1114 PCPPNCPDEV1124 YQLMRKCWEF 1134 QPSNRTSFQN1144 LIEGFEALLK1154
|
|||||
|
|
LEU881
3.536
GLY882
3.199
GLU883
3.364
GLY884
2.866
HIS885
4.598
GLY887
3.122
LYS888
3.900
VAL889
3.146
ALA906
3.213
LYS908
3.395
VAL938
4.070
MET956
3.822
|
|||||
| Ligand Name: PF-04965842 | Ligand Info | |||||
| Structure Description | Crystal Structure of JAK1 in complex with compound 25 | PDB:6BBU | ||||
| Method | X-ray diffraction | Resolution | 2.08 Å | Mutation | No | [5] |
| PDB Sequence |
PTHFEKRFLK
876 RIRDLGEGHF886 GKVELCRYDP896 EGDNTGEQVA906 VKSLKPNHIA920 DLKKEIEILR 930 NLYHENIVKY940 KGICTENGIK953 LIMEFLPSGS963 LKEYLPKNKN973 KINLKQQLKY 983 AVQICKGMDY993 LGSRQYVHRD1003 LAARNVLVES1013 EHQVKIGDFG1023 LTKAIETDKE 1033 TVKDDRDSPV1045 FWYAPECLMQ1055 SKFYIASDVW1065 SFGVTLHELL1075 TYCDSDSSPM 1085 ALFLKMIGPT1095 HGQMTVTRLV1105 NTLKEGKRLP1115 CPPNCPDEVY1125 QLMRKCWEFQ 1135 PSNRTSFQNL1145 IEGFEALLK
|
|||||
|
|
LEU881
2.653
GLY882
3.251
GLU883
2.812
GLY884
2.901
GLY887
3.122
LYS888
3.558
VAL889
3.071
ALA906
3.343
LYS908
2.820
VAL938
3.527
MET956
2.965
GLU957
1.817
|
|||||
| Click to View More Binding Site Information of This Target with Different Ligands | ||||||
| Different Human System Profiles of Target | Top |
|---|---|
|
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
|
|
|
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.
|
| KEGG Pathway | Pathway ID | Affiliated Target | Pathway Map |
|---|---|---|---|
| PI3K-Akt signaling pathway | hsa04151 | Affiliated Target |
|
| Class: Environmental Information Processing => Signal transduction | Pathway Hierarchy | ||
| Necroptosis | hsa04217 | Affiliated Target |
|
| Class: Cellular Processes => Cell growth and death | Pathway Hierarchy | ||
| Osteoclast differentiation | hsa04380 | Affiliated Target |
|
| Class: Organismal Systems => Development and regeneration | Pathway Hierarchy | ||
| Signaling pathways regulating pluripotency of stem cells | hsa04550 | Affiliated Target |
|
| Class: Cellular Processes => Cellular community - eukaryotes | Pathway Hierarchy | ||
| NOD-like receptor signaling pathway | hsa04621 | Affiliated Target |
|
| Class: Organismal Systems => Immune system | Pathway Hierarchy | ||
| JAK-STAT signaling pathway | hsa04630 | Affiliated Target |
|
| Class: Environmental Information Processing => Signal transduction | Pathway Hierarchy | ||
| Th1 and Th2 cell differentiation | hsa04658 | Affiliated Target |
|
| Class: Organismal Systems => Immune system | Pathway Hierarchy | ||
| Th17 cell differentiation | hsa04659 | Affiliated Target |
|
| Class: Organismal Systems => Immune system | Pathway Hierarchy | ||
| Click to Show/Hide the Information of Affiliated Human Pathways | |||
| Degree | 50 | Degree centrality | 5.37E-03 | Betweenness centrality | 2.00E-03 |
|---|---|---|---|---|---|
| Closeness centrality | 2.41E-01 | Radiality | 1.42E+01 | Clustering coefficient | 1.27E-01 |
| Neighborhood connectivity | 3.00E+01 | Topological coefficient | 5.76E-02 | Eccentricity | 12 |
| Download | Click to Download the Full PPI Network of This Target | ||||
| Chemical Structure based Activity Landscape of Target | Top |
|---|---|
| Co-Targets | Top | |||||
|---|---|---|---|---|---|---|
| Co-Targets | ||||||
| Target Poor or Non Binders | Top | |||||
|---|---|---|---|---|---|---|
| Target Poor or Non Binders | ||||||
| References | Top | |||||
|---|---|---|---|---|---|---|
| REF 1 | The Use of Anti-Inflammatory Drugs in the Treatment of People With Severe Coronavirus Disease 2019 (COVID-19): The Perspectives of Clinical Immunologists From China. Clin Immunol. 2020 May;214:108393. | |||||
| REF 2 | Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services. 2015 | |||||
| REF 3 | FDA Approved Drug Products from FDA Official Website. 2019. Application Number: (NDA) 202192 | |||||
| REF 4 | Dissecting specificity in the Janus kinases: the structures of JAK-specific inhibitors complexed to the JAK1 and JAK2 protein tyrosine kinase domains. J Mol Biol. 2009 Mar 20;387(1):219-32. | |||||
| REF 5 | Identification of N-{cis-3-[Methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]cyclobutyl}propane-1-sulfonamide (PF-04965842): A Selective JAK1 Clinical Candidate for the Treatment of Autoimmune Diseases. J Med Chem. 2018 Feb 8;61(3):1130-1152. | |||||
If You Find Any Error in Data or Bug in Web Service, Please Kindly Report It to Dr. Zhou and Dr. Zhang.