Target Information
Target General Information | Top | |||||
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Target ID |
T64553
(Former ID: TTDI02371)
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Target Name |
Tyrosine-protein kinase ZAP-70 (ZAP-70)
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Synonyms |
Syk-related tyrosine kinase; SRK; 70 kDa zeta-chain associated protein
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Gene Name |
ZAP70
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Target Type |
Patented-recorded target
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[1] | ||||
Function |
Regulates motility, adhesion and cytokine expression of mature T-cells, as well as thymocyte development. Contributes also to the development and activation of primary B-lymphocytes. When antigen presenting cells (APC) activate T-cell receptor (TCR), a serie of phosphorylations lead to the recruitment of ZAP70 to the doubly phosphorylated TCR component CD247/CD3Z through ITAM motif at the plasma membrane. This recruitment serves to localization to the stimulated TCR and to relieve its autoinhibited conformation. Release of ZAP70 active conformation is further stabilized by phosphorylation mediated by LCK. Subsequently, ZAP70 phosphorylates at least 2 essential adapter proteins: LAT and LCP2. In turn, a large number of signaling molecules are recruited and ultimately lead to lymphokine production, T-cell proliferation and differentiation. Furthermore, ZAP70 controls cytoskeleton modifications, adhesion and mobility of T-lymphocytes, thus ensuring correct delivery of effectors to the APC. ZAP70 is also required for TCR-CD247/CD3Z internalization and degradation through interaction with the E3 ubiquitin-protein ligase CBL and adapter proteins SLA and SLA2. Thus, ZAP70 regulates both T-cell activation switch on and switch off by modulating TCR expression at the T-cell surface. During thymocyte development, ZAP70 promotes survival and cell-cycle progression of developing thymocytes before positive selection (when cells are still CD4/CD8 double negative). Additionally, ZAP70-dependent signaling pathway may also contribute to primary B-cells formation and activation through B-cell receptor (BCR). Tyrosine kinase that plays an essential role in regulation of the adaptive immune response.
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BioChemical Class |
Kinase
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UniProt ID | ||||||
EC Number |
EC 2.7.10.2
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Sequence |
MPDPAAHLPFFYGSISRAEAEEHLKLAGMADGLFLLRQCLRSLGGYVLSLVHDVRFHHFP
IERQLNGTYAIAGGKAHCGPAELCEFYSRDPDGLPCNLRKPCNRPSGLEPQPGVFDCLRD AMVRDYVRQTWKLEGEALEQAIISQAPQVEKLIATTAHERMPWYHSSLTREEAERKLYSG AQTDGKFLLRPRKEQGTYALSLIYGKTVYHYLISQDKAGKYCIPEGTKFDTLWQLVEYLK LKADGLIYCLKEACPNSSASNASGAAAPTLPAHPSTLTHPQRRIDTLNSDGYTPEPARIT SPDKPRPMPMDTSVYESPYSDPEELKDKKLFLKRDNLLIADIELGCGNFGSVRQGVYRMR KKQIDVAIKVLKQGTEKADTEEMMREAQIMHQLDNPYIVRLIGVCQAEALMLVMEMAGGG PLHKFLVGKREEIPVSNVAELLHQVSMGMKYLEEKNFVHRDLAARNVLLVNRHYAKISDF GLSKALGADDSYYTARSAGKWPLKWYAPECINFRKFSSRSDVWSYGVTMWEALSYGQKPY KKMKGPEVMAFIEQGKRMECPPECPPELYALMSDCWIYKWEDRPDFLTVEQRMRACYYSL ASKVEGPPGSTQKAEAACA Click to Show/Hide
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3D Structure | Click to Show 3D Structure of This Target | PDB |
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 Regulators | Top | |||||
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Target-regulating microRNAs | ||||||
Target-interacting Proteins |
Target Affiliated Biological Pathways | Top | |||||
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KEGG Pathway | [+] 5 KEGG Pathways | + | ||||
1 | Ras signaling pathway | |||||
2 | NF-kappa B signaling pathway | |||||
3 | Natural killer cell mediated cytotoxicity | |||||
4 | T cell receptor signaling pathway | |||||
5 | Primary immunodeficiency | |||||
Panther Pathway | [+] 1 Panther Pathways | + | ||||
1 | T cell activation | |||||
PID Pathway | [+] 5 PID Pathways | + | ||||
1 | TCR signaling in naï | |||||
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3 | TCR signaling in naï | |||||
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5 | Class I PI3K signaling events | |||||
Reactome | [+] 2 Reactome Pathways | + | ||||
1 | Translocation of ZAP-70 to Immunological synapse | |||||
2 | Generation of second messenger molecules | |||||
WikiPathways | [+] 6 WikiPathways | + | ||||
1 | TCR Signaling Pathway | |||||
2 | Interferon type I signaling pathways | |||||
3 | Inflammatory Response Pathway | |||||
4 | JAK/STAT | |||||
5 | T-Cell Receptor and Co-stimulatory Signaling | |||||
6 | TCR signaling |
References | Top | |||||
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REF 1 | Synthetic studies on novel Syk inhibitors. Part 1: Synthesis and structure-activity relationships of pyrimidine-5-carboxamide derivatives. Bioorg Med Chem. 2005 Aug 15;13(16):4936-51. | |||||
REF 2 | Compounds and compositions as kinase inhibitors. US8546370. | |||||
REF 3 | Identification of binding specificity-determining features in protein families. J Med Chem. 2012 Mar 8;55(5):1926-39. |
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