View source for 1u59


==Crystal Structure of the ZAP-70 Kinase Domain in Complex with Staurosporine==
<StructureSection load='1u59' size='340' side='right'caption='[[1u59]], [[Resolution|resolution]] 2.30&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[1u59]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1U59 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=1U59 FirstGlance]. <br>
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.3&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=STU:STAUROSPORINE'>STU</scene></td></tr>
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=1u59 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1u59 OCA], [https://pdbe.org/1u59 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=1u59 RCSB], [https://www.ebi.ac.uk/pdbsum/1u59 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=1u59 ProSAT]</span></td></tr>
</table>
== Disease ==
[https://www.uniprot.org/uniprot/ZAP70_HUMAN ZAP70_HUMAN] Defects in ZAP70 are the cause of selective T-cell defect (STCD) [MIM:[https://omim.org/entry/269840 269840]. A form of severe combined immunodeficiency characterized by a selective absence of CD8+ T cells.<ref>PMID:8124727</ref> <ref>PMID:8202713</ref> <ref>PMID:11412303</ref> <ref>PMID:11123350</ref> <ref>PMID:18509675</ref> 
== Function ==
[https://www.uniprot.org/uniprot/ZAP70_HUMAN ZAP70_HUMAN] Tyrosine kinase that plays an essential role in regulation of the adaptive immune response. 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).<ref>PMID:1423621</ref> <ref>PMID:8124727</ref> <ref>PMID:8702662</ref> <ref>PMID:9489702</ref> <ref>PMID:11353765</ref> 
== Evolutionary Conservation ==
[[Image:Consurf_key_small.gif|200px|right]]
Check<jmol>
  <jmolCheckbox>
    <scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/u5/1u59_consurf.spt"</scriptWhenChecked>
    <scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked>
    <text>to colour the structure by Evolutionary Conservation</text>
  </jmolCheckbox>
</jmol>, as determined by [http://consurfdb.tau.ac.il/ ConSurfDB]. You may read the [[Conservation%2C_Evolutionary|explanation]] of the method and the full data available from [http://bental.tau.ac.il/new_ConSurfDB/main_output.php?pdb_ID=1u59 ConSurf].
<div style="clear:both"></div>
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== Publication Abstract from PubMed ==
The ZAP-70 tyrosine kinase plays a critical role in T cell activation and the immune response and therefore is a logical target for immunomodulatory therapies. Although the crystal structure of the tandem Src homology-2 domains of human ZAP-70 in complex with a peptide derived from the zeta subunit of the T cell receptor has been reported (Hatada, M. H., Lu, X., Laird, E. R., Green, J., Morgenstern, J. P., Lou, M., Marr, C. S., Phillips, T. B., Ram, M. K., Theriault, K., Zoller, M. J., and Karas, J. L. (1995) Nature 377, 32-38), the structure of the kinase domain has been elusive to date. We crystallized and determined the three-dimensional structure of the catalytic subunit of ZAP-70 as a complex with staurosporine to 2.3 A resolution, utilizing an active kinase domain containing residues 327-606 identified by systematic N- and C-terminal truncations. The crystal structure shows that this ZAP-70 kinase domain is in an active-like conformation despite the lack of tyrosine phosphorylation in the activation loop. The unique features of the ATP-binding site, identified by structural and sequence comparison with other kinases, will be useful in the design of ZAP-70-selective inhibitors.

The three-dimensional structure of the ZAP-70 kinase domain in complex with staurosporine: implications for the design of selective inhibitors.,Jin L, Pluskey S, Petrella EC, Cantin SM, Gorga JC, Rynkiewicz MJ, Pandey P, Strickler JE, Babine RE, Weaver DT, Seidl KJ J Biol Chem. 2004 Oct 8;279(41):42818-25. Epub 2004 Jul 29. PMID:15292186<ref>PMID:15292186</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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<div class="pdbe-citations 1u59" style="background-color:#fffaf0;"></div>

==See Also==
*[[Tyrosine kinase 3D structures|Tyrosine kinase 3D structures]]
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Babine RE]]
[[Category: Cantin SM]]
[[Category: Gorga JC]]
[[Category: Jin L]]
[[Category: Pandey P]]
[[Category: Petrella EC]]
[[Category: Pluskey S]]
[[Category: Rynkiewicz MJ]]
[[Category: Seidl KJ]]
[[Category: Strickler JE]]
[[Category: Weaver DT]]