View source for 4ppb


==ITK kinase domain with compound 28 (N-{1-[(1S)-3-(DIMETHYLAMINO)-1-PHENYLPROPYL]-1H-PYRAZOL-4-YL}-6-(1H-PYRAZOL-4-YL)-1H-INDAZOLE-3-CARBOXAMIDE)==
<StructureSection load='4ppb' size='340' side='right' caption='[[4ppb]], [[Resolution|resolution]] 2.82&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[4ppb]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4PPB OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4PPB FirstGlance]. <br>
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=2VV:N-{1-[(1S)-3-(DIMETHYLAMINO)-1-PHENYLPROPYL]-1H-PYRAZOL-4-YL}-6-(1H-PYRAZOL-4-YL)-1H-INDAZOLE-3-CARBOXAMIDE'>2VV</scene></td></tr>
<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[4pp9|4pp9]], [[4ppa|4ppa]], [[4ppc|4ppc]]</td></tr>
<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Non-specific_protein-tyrosine_kinase Non-specific protein-tyrosine kinase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.10.2 2.7.10.2] </span></td></tr>
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4ppb FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4ppb OCA], [http://pdbe.org/4ppb PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4ppb RCSB], [http://www.ebi.ac.uk/pdbsum/4ppb PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4ppb ProSAT]</span></td></tr>
</table>
== Disease ==
[[http://www.uniprot.org/uniprot/ITK_HUMAN ITK_HUMAN]] Defects in ITK are the cause of lymphoproliferative syndrome EBV-associated autosomal type 1 (LPSA1) [MIM:[http://omim.org/entry/613011 613011]]. LPSA1 is a rare immunodeficiency characterized by extreme susceptibility to infection with Epstein-Barr virus (EBV). Inadequate immune response to EBV can have a fatal outcome. Clinical features include splenomegaly, lymphadenopathy, anemia, thrombocytopenia, pancytopenia, recurrent infections. There is an increased risk for lymphoma.<ref>PMID:19425169</ref>  
== Function ==
[[http://www.uniprot.org/uniprot/ITK_HUMAN ITK_HUMAN]] Tyrosine kinase that plays an essential role in regulation of the adaptive immune response. Regulates the development, function and differentiation of conventional T-cells and nonconventional NKT-cells. When antigen presenting cells (APC) activate T-cell receptor (TCR), a series of phosphorylation lead to the recruitment of ITK to the cell membrane, in the vicinity of the stimulated TCR receptor, where it is phosphorylated by LCK. Phosphorylation leads to ITK autophosphorylation and full activation. Once activated, phosphorylates PLCG1, leading to the activation of this lipase and subsequent cleavage of its substrates. In turn, the endoplasmic reticulum releases calcium in the cytoplasm and the nuclear activator of activated T-cells (NFAT) translocates into the nucleus to perform its transcriptional duty. Phosphorylates 2 essential adapter proteins: the linker for activation of T-cells/LAT protein and LCP2. Then, a large number of signaling molecules such as VAV1 are recruited and ultimately lead to lymphokine production, T-cell proliferation and differentiation.<ref>PMID:12186560</ref> <ref>PMID:12682224</ref> <ref>PMID:21725281</ref>  
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
There is evidence that small molecule inhibitors of the non-receptor tyrosine kinase ITK, a component of the T-cell receptor signaling cascade, could represent a novel asthma therapeutic class. Moreover, given the expected chronic dosing regimen of any asthma treatment, highly selective as well as potent inhibitors would be strongly preferred in any potential therapeutic. Here we report hit-to-lead optimization of a series of indazoles that demonstrate sub-nanomolar inhibitory potency against ITK with strong cellular activity and good kinase selectivity. We also elucidate the binding mode of these inhibitors by solving the X-ray crystal structures of the complexes.

Discovery and optimization of indazoles as potent and selective interleukin-2 inducible T cell kinase (ITK) inhibitors.,Pastor RM, Burch JD, Magnuson S, Ortwine DF, Chen Y, De La Torre K, Ding X, Eigenbrot C, Johnson A, Liimatta M, Liu Y, Shia S, Wang X, Wu LC, Pei Z Bioorg Med Chem Lett. 2014 Jun 1;24(11):2448-52. doi: 10.1016/j.bmcl.2014.04.023., Epub 2014 Apr 16. PMID:24767842<ref>PMID:24767842</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 4ppb" style="background-color:#fffaf0;"></div>

==See Also==
*[[Tyrosine kinase|Tyrosine kinase]]
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Non-specific protein-tyrosine kinase]]
[[Category: Eigenbrot, C]]
[[Category: Shia, S]]
[[Category: Protein kinase]]
[[Category: Transferase-transferase inhibitor complex]]