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| - | {{STRUCTURE_3v8w| PDB=3v8w | SCENE= }} | |
| - | ===Crystal Structure of Interleukin-2 Inducible T-cell Kinase Itk Catalytic Domain with Thienopyrazolylindole Inhibitor 469=== | |
| - | {{ABSTRACT_PUBMED_22464456}} | |
| | | | |
| - | ==Disease== | + | ==Crystal Structure of Interleukin-2 Inducible T-cell Kinase Itk Catalytic Domain with Thienopyrazolylindole Inhibitor 469== |
| - | [[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> | + | <StructureSection load='3v8w' size='340' side='right'caption='[[3v8w]], [[Resolution|resolution]] 2.27Å' scene=''> |
| | + | == Structural highlights == |
| | + | <table><tr><td colspan='2'>[[3v8w]] is a 2 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=3V8W OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3V8W 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]] 2.27Å</td></tr> |
| | + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=0G2:3-[2-(5-PHENYL-2H-THIENO[3,2-C]PYRAZOL-3-YL)-1H-INDOL-6-YL]PENTAN-3-OL'>0G2</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</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=3v8w FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3v8w OCA], [https://pdbe.org/3v8w PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3v8w RCSB], [https://www.ebi.ac.uk/pdbsum/3v8w PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3v8w ProSAT]</span></td></tr> |
| | + | </table> |
| | + | == Disease == |
| | + | [https://www.uniprot.org/uniprot/ITK_HUMAN ITK_HUMAN] Defects in ITK are the cause of lymphoproliferative syndrome EBV-associated autosomal type 1 (LPSA1) [MIM:[https://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 == |
| | + | [https://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> |
| | | | |
| - | ==Function== | + | ==See Also== |
| - | [[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> | + | *[[Tyrosine kinase 3D structures|Tyrosine kinase 3D structures]] |
| - | | + | == References == |
| - | ==About this Structure==
| + | <references/> |
| - | [[3v8w]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3V8W OCA].
| + | __TOC__ |
| - | | + | </StructureSection> |
| - | ==Reference== | + | |
| - | <ref group="xtra">PMID:022464456</ref><references group="xtra"/><references/>
| + | |
| | [[Category: Homo sapiens]] | | [[Category: Homo sapiens]] |
| - | [[Category: Non-specific protein-tyrosine kinase]] | + | [[Category: Large Structures]] |
| - | [[Category: McLean, L R.]] | + | [[Category: McLean LR]] |
| - | [[Category: Zhang, Y.]] | + | [[Category: Zhang Y]] |
| - | [[Category: Kinase]]
| + | |
| - | [[Category: Transferase-transferase inhibitor complex]]
| + | |
| Structural highlights
Disease
ITK_HUMAN Defects in ITK are the cause of lymphoproliferative syndrome EBV-associated autosomal type 1 (LPSA1) [MIM: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.[1]
Function
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.[2] [3] [4]
See Also
References
- ↑ Huck K, Feyen O, Niehues T, Ruschendorf F, Hubner N, Laws HJ, Telieps T, Knapp S, Wacker HH, Meindl A, Jumaa H, Borkhardt A. Girls homozygous for an IL-2-inducible T cell kinase mutation that leads to protein deficiency develop fatal EBV-associated lymphoproliferation. J Clin Invest. 2009 May;119(5):1350-8. PMID:19425169
- ↑ Perez-Villar JJ, Whitney GS, Sitnick MT, Dunn RJ, Venkatesan S, O'Day K, Schieven GL, Lin TA, Kanner SB. Phosphorylation of the linker for activation of T-cells by Itk promotes recruitment of Vav. Biochemistry. 2002 Aug 27;41(34):10732-40. PMID:12186560
- ↑ Grasis JA, Browne CD, Tsoukas CD. Inducible T cell tyrosine kinase regulates actin-dependent cytoskeletal events induced by the T cell antigen receptor. J Immunol. 2003 Apr 15;170(8):3971-6. PMID:12682224
- ↑ Sela M, Bogin Y, Beach D, Oellerich T, Lehne J, Smith-Garvin JE, Okumura M, Starosvetsky E, Kosoff R, Libman E, Koretzky G, Kambayashi T, Urlaub H, Wienands J, Chernoff J, Yablonski D. Sequential phosphorylation of SLP-76 at tyrosine 173 is required for activation of T and mast cells. EMBO J. 2011 Jul 1;30(15):3160-72. doi: 10.1038/emboj.2011.213. PMID:21725281 doi:10.1038/emboj.2011.213
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