zeta chain of T cell receptor associated protein kinase 70 | Syk family | IUPHAR Guide to IMMUNOPHARMACOLOGY

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zeta chain of T cell receptor associated protein kinase 70

  Target has curated data in GtoImmuPdb

Target id: 2285

Nomenclature: zeta chain of T cell receptor associated protein kinase 70

Abbreviated Name: ZAP70

Family: Syk family

Annotation status:  image of an orange circle Annotated and awaiting review. Please contact us if you can help with reviewing.  » Email us

Gene and Protein Information
Species TM AA Chromosomal Location Gene Symbol Gene Name Reference
Human - 619 2q11.2 ZAP70 zeta chain of T cell receptor associated protein kinase 70
Mouse - 618 1 A4-C1 Zap70 zeta-chain (TCR) associated protein kinase
Rat - 614 9 q21 Zap70 zeta chain of T cell receptor associated protein kinase 70
Previous and Unofficial Names
SRK | STD | syk-related protein tyrosine kinase | TZK | zeta chain of T cell receptor associated protein kinase 70kDa | zeta-chain (TCR) associated protein kinase 70 | zeta chain of T-cell receptor associated protein kinase 70
Database Links
BRENDA
CATH/Gene3D
Ensembl Gene
Entrez Gene
Human Protein Atlas
KEGG Enzyme
KEGG Gene
OMIM
Orphanet
RefSeq Nucleotide
RefSeq Protein
UniProtKB
Wikipedia
Selected 3D Structures
Image of receptor 3D structure from RCSB PDB
Description:  Crystal structure of the apo SH2 domains of ZAP-70.
PDB Id:  1M61
Resolution:  2.5Å
Species:  Human
References:  6
Image of receptor 3D structure from RCSB PDB
Description:  Autoinhibited intact human ZAP-70.
PDB Id:  2OZO
Resolution:  2.6Å
Species:  Human
References:  5
Image of receptor 3D structure from RCSB PDB
Description:  Crystal structure of the ZAP-70 kinase domain in complex with staurosporine.
PDB Id:  1U59
Ligand:  staurosporine
Resolution:  2.3Å
Species:  Human
References:  9
Enzyme Reaction
EC Number: 2.7.10.2

Download all structure-activity data for this target as a CSV file

Inhibitors
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Affinity Parameter Reference
aloisine Hs Inhibition 5.6 pKi 2
pKi 5.6 (Ki 2.63x10-6 M) [2]
TAK-659 Hs Inhibition 7.1 pIC50 10
pIC50 7.1 (IC50 7.5x10-8 M) [10]
Description: Measured in a time-resolved fluorescence resonance energy transfer (TR-FRET) assay.
Syk inhibitor II Hs Inhibition 4.9 pIC50 8
pIC50 4.9 (IC50 1.12x10-5 M) [8]
DiscoveRx KINOMEscan® screen
A screen of 72 inhibitors against 456 human kinases. Quantitative data were derived using DiscoveRx KINOMEscan® platform.
http://www.discoverx.com/services/drug-discovery-development-services/kinase-profiling/kinomescan
Reference: 4,11

Key to terms and symbols Click column headers to sort
Target used in screen: ZAP70
Ligand Sp. Type Action Affinity Parameter
lestaurtinib Hs Inhibitor Inhibition 7.8 pKd
tamatinib Hs Inhibitor Inhibition 7.7 pKd
staurosporine Hs Inhibitor Inhibition 7.4 pKd
KW-2449 Hs Inhibitor Inhibition 6.0 pKd
NVP-TAE684 Hs Inhibitor Inhibition 5.8 pKd
bosutinib Hs Inhibitor Inhibition 5.8 pKd
midostaurin Hs Inhibitor Inhibition 5.6 pKd
SB203580 Hs Inhibitor Inhibition <5.5 pKd
ruboxistaurin Hs Inhibitor Inhibition <5.5 pKd
erlotinib Hs Inhibitor Inhibition <5.5 pKd
Displaying the top 10 most potent ligands  View all ligands in screen »
EMD Millipore KinaseProfilerTM screen/Reaction Biology Kinase HotspotSM screen
A screen profiling 158 kinase inhibitors (Calbiochem Protein Kinase Inhibitor Library I and II, catalogue numbers 539744 and 539745) for their inhibitory activity at 1µM and 10µM against 234 human recombinant kinases using the EMD Millipore KinaseProfilerTM service.

A screen profiling the inhibitory activity of 178 commercially available kinase inhibitors at 0.5µM against a panel of 300 recombinant protein kinases using the Reaction Biology Corporation Kinase HotspotSM platform.

http://www.millipore.com/techpublications/tech1/pf3036
http://www.reactionbiology.com/webapps/main/pages/kinase.aspx


Reference: 1,7

Key to terms and symbols Click column headers to sort
Target used in screen: ZAP-70/ZAP70
Ligand Sp. Type Action % Activity remaining at 0.5µM % Activity remaining at 1µM % Activity remaining at 10µM
staurosporine Hs Inhibitor Inhibition 5.4 5.5 0.0
K-252a Hs Inhibitor Inhibition 22.8 16.0 2.0
midostaurin Hs Inhibitor Inhibition 65.4 70.0 60.0
PDK1/Akt/Flt dual pathway inhibitor Hs Inhibitor Inhibition 68.2 111.0 120.0
aloisine Hs Inhibitor Inhibition 74.2 111.0 90.0
Gö 6976 Hs Inhibitor Inhibition 77.7 81.0 111.0
CGP53353 Hs Inhibitor Inhibition 78.8 113.0 119.0
PP1 analog II Hs Inhibitor Inhibition 84.6 97.0 110.0
KN-93 Hs Inhibitor Inhibition 84.7 105.0 97.0
Cdk1/2 inhibitor III Hs Inhibitor Inhibition 86.9 124.0 86.0
Displaying the top 10 most potent ligands  View all ligands in screen »
Immunopharmacology Comments
ZAP-70 has much lower intrinsic enzyme activity than SYK, and expression is restricted to T cells and NK cells [3]. This kinase binds directly to the T cell receptor (TCR) and is essential for TCR signalling and T cell activation. ZAP-70-deficiency causes severe combined immunodeficiency in mice and humans.
Immuno Process Associations
Immuno Process:  Inflammation
GO Annotations:  Associated to 2 GO processes
GO:0045087 innate immune response IBA
GO:0072678 T cell migration TAS
Immuno Process:  T cell (activation)
GO Annotations:  Associated to 9 GO processes
GO:0002250 adaptive immune response TAS
GO:0030217 T cell differentiation NAS
GO:0042110 T cell activation TAS
GO:0045059 positive thymic T cell selection IDA
GO:0045582 positive regulation of T cell differentiation IDA
click arrow to show/hide IEA associations
GO:0043366 beta selection IEA
GO:0045060 negative thymic T cell selection IEA
GO:0046638 positive regulation of alpha-beta T cell differentiation IEA
GO:0046641 positive regulation of alpha-beta T cell proliferation IEA
Immuno Process:  B cell (activation)
GO Annotations:  Associated to 2 GO processes
GO:0002250 adaptive immune response TAS
GO:0042113 B cell activation TAS
Immuno Process:  Immune regulation
GO Annotations:  Associated to 4 GO processes
GO:0045582 positive regulation of T cell differentiation IDA
GO:0050852 T cell receptor signaling pathway TAS
click arrow to show/hide IEA associations
GO:0046638 positive regulation of alpha-beta T cell differentiation IEA
GO:0046641 positive regulation of alpha-beta T cell proliferation IEA
Immuno Process:  Immune system development
GO Annotations:  Associated to 6 GO processes
GO:0030217 T cell differentiation NAS
GO:0045059 positive thymic T cell selection IDA
GO:0045582 positive regulation of T cell differentiation IDA
click arrow to show/hide IEA associations
GO:0043366 beta selection IEA
GO:0045060 negative thymic T cell selection IEA
GO:0046638 positive regulation of alpha-beta T cell differentiation IEA
Immuno Process:  Chemotaxis & migration
GO Annotations:  Associated to 5 GO processes
GO:0045582 positive regulation of T cell differentiation IDA
GO:0070489 T cell aggregation TAS
GO:0072678 T cell migration TAS
click arrow to show/hide IEA associations
GO:0046638 positive regulation of alpha-beta T cell differentiation IEA
GO:0046641 positive regulation of alpha-beta T cell proliferation IEA
Immuno Process:  Cellular signalling
GO Annotations:  Associated to 10 GO processes
GO:0030217 T cell differentiation NAS
GO:0042110 T cell activation TAS
GO:0042113 B cell activation TAS
GO:0045059 positive thymic T cell selection IDA
GO:0045582 positive regulation of T cell differentiation IDA
GO:0050852 T cell receptor signaling pathway TAS
click arrow to show/hide IEA associations
GO:0043366 beta selection IEA
GO:0045060 negative thymic T cell selection IEA
GO:0046638 positive regulation of alpha-beta T cell differentiation IEA
GO:0046641 positive regulation of alpha-beta T cell proliferation IEA
Clinically-Relevant Mutations and Pathophysiology
Disease:  Selective T-cell defect
Synonyms: Combined immunodeficiency due to ZAP70 deficiency [Orphanet: ORPHA911]
OMIM: 269840
Orphanet: ORPHA911

References

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1. Anastassiadis T, Deacon SW, Devarajan K, Ma H, Peterson JR. (2011) Comprehensive assay of kinase catalytic activity reveals features of kinase inhibitor selectivity. Nat. Biotechnol., 29 (11): 1039-45. [PMID:22037377]

2. Anderson PC, De Sapio V, Turner KB, Elmer SP, Roe DC, Schoeniger JS. (2012) Identification of binding specificity-determining features in protein families. J. Med. Chem., 55 (5): 1926-39. [PMID:22289061]

3. Au-Yeung BB, Deindl S, Hsu LY, Palacios EH, Levin SE, Kuriyan J, Weiss A. (2009) The structure, regulation, and function of ZAP-70. Immunol. Rev., 228 (1): 41-57. [PMID:19290920]

4. Davis MI, Hunt JP, Herrgard S, Ciceri P, Wodicka LM, Pallares G, Hocker M, Treiber DK, Zarrinkar PP. (2011) Comprehensive analysis of kinase inhibitor selectivity. Nat. Biotechnol., 29 (11): 1046-51. [PMID:22037378]

5. Deindl S, Kadlecek TA, Brdicka T, Cao X, Weiss A, Kuriyan J. (2007) Structural basis for the inhibition of tyrosine kinase activity of ZAP-70. Cell, 129 (4): 735-46. [PMID:17512407]

6. Folmer RH, Geschwindner S, Xue Y. (2002) Crystal structure and NMR studies of the apo SH2 domains of ZAP-70: two bikes rather than a tandem. Biochemistry, 41 (48): 14176-84. [PMID:12450381]

7. Gao Y, Davies SP, Augustin M, Woodward A, Patel UA, Kovelman R, Harvey KJ. (2013) A broad activity screen in support of a chemogenomic map for kinase signalling research and drug discovery. Biochem. J., 451 (2): 313-28. [PMID:23398362]

8. Hisamichi H, Naito R, Toyoshima A, Kawano N, Ichikawa A, Orita A, Orita M, Hamada N, Takeuchi M, Ohta M et al.. (2005) Synthetic studies on novel Syk inhibitors. Part 1: Synthesis and structure-activity relationships of pyrimidine-5-carboxamide derivatives. Bioorg. Med. Chem., 13 (16): 4936-51. [PMID:15990316]

9. Jin L, Pluskey S, Petrella EC, Cantin SM, Gorga JC, Rynkiewicz MJ, Pandey P, Strickler JE, Babine RE, Weaver DT et al.. (2004) The three-dimensional structure of the ZAP-70 kinase domain in complex with staurosporine: implications for the design of selective inhibitors. J. Biol. Chem., 279 (41): 42818-25. [PMID:15292186]

10. Lam B, Arikawa Y, Cramlett J, Dong Q, de Jong R, Feher V, Grimshaw CE, Farrell PJ, Hoffman ID, Jennings A et al.. (2016) Discovery of TAK-659 an orally available investigational inhibitor of Spleen Tyrosine Kinase (SYK). Bioorg. Med. Chem. Lett., 26 (24): 5947-5950. [PMID:27839918]

11. Wodicka LM, Ciceri P, Davis MI, Hunt JP, Floyd M, Salerno S, Hua XH, Ford JM, Armstrong RC, Zarrinkar PP et al.. (2010) Activation state-dependent binding of small molecule kinase inhibitors: structural insights from biochemistry. Chem. Biol., 17 (11): 1241-9. [PMID:21095574]

How to cite this page

Syk family: zeta chain of T cell receptor associated protein kinase 70. Last modified on 27/02/2018. Accessed on 16/02/2019. IUPHAR/BPS Guide to PHARMACOLOGY, http://www.guidetoimmunopharmacology.org/GRAC/ObjectDisplayForward?objectId=2285.