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zeta chain of T cell receptor associated protein kinase 70

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Target id: 2285

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

Abbreviated Name: ZAP70

Family: Syk family

Contents:

Gene and Protein Information Click here for help
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 15.41 cM 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 Click here for help
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 Click here for help
Alphafold P43403 (Hs), P43404 (Mm)
BRENDA 2.7.10.2
CATH/Gene3D 3.30.505.10, 1.10.930.10
ChEMBL Target CHEMBL2803 (Hs), CHEMBL2034801 (Mm)
Ensembl Gene ENSG00000115085 (Hs), ENSMUSG00000026117 (Mm), ENSRNOG00000016995 (Rn)
Entrez Gene 7535 (Hs), 22637 (Mm), 301348 (Rn)
Human Protein Atlas ENSG00000115085 (Hs)
KEGG Enzyme 2.7.10.2
KEGG Gene hsa:7535 (Hs), mmu:22637 (Mm), rno:301348 (Rn)
OMIM 176947 (Hs)
Orphanet ORPHA120579 (Hs)
Pharos P43403 (Hs)
RefSeq Nucleotide NM_001079 (Hs), NM_009539 (Mm), NM_001012002 (Rn)
RefSeq Protein NP_001070 (Hs), NP_033565 (Mm), NP_001012002 (Rn)
UniProtKB P43403 (Hs), P43404 (Mm)
Wikipedia ZAP70 (Hs)
Selected 3D Structures Click here for help
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 Click here for help
EC Number: 2.7.10.2

Download all structure-activity data for this target as a CSV file go icon to follow link

Inhibitors
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Value Parameter Reference
aloisine Small molecule or natural product Click here for species-specific activity table Hs Inhibition 5.6 pKi 2
⤷ pKi 5.6 (Ki 2.63x10-6 M) [2]
mivavotinib Small molecule or natural product Click here for species-specific activity table Ligand has a PDB structure Immunopharmacology Ligand 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 Small molecule or natural product Click here for species-specific activity table Immunopharmacology Ligand Hs Inhibition 4.9 pIC50 8
⤷ pIC50 4.9 (IC50 1.12x10-5 M) [8]
DiscoveRx KINOMEscan® screen Click here for help
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 Value Parameter
lestaurtinib Small molecule or natural product Ligand has a PDB structure Immunopharmacology Ligand Hs Inhibitor Inhibition 7.8 pKd
tamatinib Small molecule or natural product Ligand has a PDB structure Immunopharmacology Ligand Hs Inhibitor Inhibition 7.7 pKd
staurosporine Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 7.4 pKd
KW-2449 Small molecule or natural product Hs Inhibitor Inhibition 6.0 pKd
NVP-TAE684 Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 5.8 pKd
bosutinib Small molecule or natural product Approved drug Ligand has a PDB structure Immunopharmacology Ligand Hs Inhibitor Inhibition 5.8 pKd
midostaurin Small molecule or natural product Approved drug Ligand has a PDB structure Immunopharmacology Ligand Hs Inhibitor Inhibition 5.6 pKd
SB203580 Small molecule or natural product Immunopharmacology Ligand Hs Inhibitor Inhibition <5.5 pKd
ruboxistaurin Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition <5.5 pKd
erlotinib Small molecule or natural product Approved drug Ligand has a PDB structure 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 Click here for help
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 Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 5.4 5.5 0.0
K-252a Small molecule or natural product Hs Inhibitor Inhibition 22.8 16.0 2.0
midostaurin Small molecule or natural product Approved drug Ligand has a PDB structure Immunopharmacology Ligand Hs Inhibitor Inhibition 65.4 70.0 60.0
PDK1/Akt/Flt dual pathway inhibitor Small molecule or natural product Hs Inhibitor Inhibition 68.2 111.0 120.0
aloisine Small molecule or natural product Hs Inhibitor Inhibition 74.2 111.0 90.0
Gö 6976 Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 77.7 81.0 111.0
CGP53353 Small molecule or natural product Hs Inhibitor Inhibition 78.8 113.0 119.0
PP1 analog II Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 84.6 97.0 110.0
KN-93 Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 84.7 105.0 97.0
Cdk1/2 inhibitor III Small molecule or natural product Ligand has a PDB structure 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
Immuno Process:  T cell (activation)
Immuno Process:  B cell (activation)
Immuno Process:  Immune regulation
Immuno Process:  Immune system development
Immuno Process:  Chemotaxis & migration
Immuno Process:  Cellular signalling
Clinically-Relevant Mutations and Pathophysiology Click here for help
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 19/04/2024. IUPHAR/BPS Guide to PHARMACOLOGY, https://www.guidetomalariapharmacology.org/GRAC/ObjectDisplayForward?objectId=2285.