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| - | {{STRUCTURE_1sm2| PDB=1sm2 | SCENE= }}
| + | ==Crystal structure of the phosphorylated Interleukin-2 tyrosine kinase catalytic domain== |
| - | ===Crystal structure of the phosphorylated Interleukin-2 tyrosine kinase catalytic domain=== | + | <StructureSection load='1sm2' size='340' side='right' caption='[[1sm2]], [[Resolution|resolution]] 2.30Å' scene=''> |
| - | {{ABSTRACT_PUBMED_14766749}}
| + | == Structural highlights == |
| | + | <table><tr><td colspan='2'>[[1sm2]] 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=1SM2 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=1SM2 FirstGlance]. <br> |
| | + | </td></tr><tr><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=STU:STAUROSPORINE'>STU</scene><br> |
| | + | <tr><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">ITK, LYK, EMT ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 Homo sapiens])</td></tr> |
| | + | <tr><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Transferase Transferase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.10.1 and 2.7.10.2 2.7.10.1 and 2.7.10.2] </span></td></tr> |
| | + | <tr><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=1sm2 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1sm2 OCA], [http://www.rcsb.org/pdb/explore.do?structureId=1sm2 RCSB], [http://www.ebi.ac.uk/pdbsum/1sm2 PDBsum]</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> |
| | + | == 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/sm/1sm2_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/chain_selection.php?pdb_ID=2ata ConSurf]. |
| | + | <div style="clear:both"></div> |
| | + | <div style="background-color:#fffaf0;"> |
| | + | == Publication Abstract from PubMed == |
| | + | Interleukin-2 tyrosine kinase, Itk, is an important member of the Tec family of non-receptor tyrosine kinases that play a central role in signaling through antigen receptors such as the T-cell receptor, B-cell receptor, and Fcepsilon. Selective inhibition of Itk may be an important way of modulating many diseases involving heightened or inappropriate activation of the immune system. In addition to an unliganded nonphophorylated Itk catalytic kinase domain, we determined the crystal structures of the phosphorylated and nonphosphorylated kinase domain bound to staurosporine, a potent broad-spectrum kinase inhibitor. These structures are useful for the design of novel, highly potent and selective Itk inhibitors and provide insight into the influence of inhibitor binding and phosphorylation on the conformation of Itk. |
| | | | |
| - | ==Disease==
| + | Crystal structures of interleukin-2 tyrosine kinase and their implications for the design of selective inhibitors.,Brown K, Long JM, Vial SC, Dedi N, Dunster NJ, Renwick SB, Tanner AJ, Frantz JD, Fleming MA, Cheetham GM J Biol Chem. 2004 Apr 30;279(18):18727-32. Epub 2004 Feb 6. PMID:14766749<ref>PMID:14766749</ref> |
| - | [[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==
| + | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> |
| - | [[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> |
| | | | |
| - | ==About this Structure== | + | ==See Also== |
| - | [[1sm2]] 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=1SM2 OCA]. | + | *[[Tyrosine kinase|Tyrosine kinase]] |
| - | | + | == References == |
| - | ==Reference== | + | <references/> |
| - | <ref group="xtra">PMID:014766749</ref><references group="xtra"/><references/>
| + | __TOC__ |
| | + | </StructureSection> |
| | [[Category: Homo sapiens]] | | [[Category: Homo sapiens]] |
| | [[Category: Transferase]] | | [[Category: Transferase]] |
| Structural highlights
1sm2 is a 2 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
| | Ligands: |
| | Gene: | ITK, LYK, EMT (Homo sapiens) |
| Activity: | Transferase, with EC number and 2.7.10.2 2.7.10.1 and 2.7.10.2 |
| Resources: | FirstGlance, OCA, RCSB, PDBsum |
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]
Evolutionary Conservation
Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.
Publication Abstract from PubMed
Interleukin-2 tyrosine kinase, Itk, is an important member of the Tec family of non-receptor tyrosine kinases that play a central role in signaling through antigen receptors such as the T-cell receptor, B-cell receptor, and Fcepsilon. Selective inhibition of Itk may be an important way of modulating many diseases involving heightened or inappropriate activation of the immune system. In addition to an unliganded nonphophorylated Itk catalytic kinase domain, we determined the crystal structures of the phosphorylated and nonphosphorylated kinase domain bound to staurosporine, a potent broad-spectrum kinase inhibitor. These structures are useful for the design of novel, highly potent and selective Itk inhibitors and provide insight into the influence of inhibitor binding and phosphorylation on the conformation of Itk.
Crystal structures of interleukin-2 tyrosine kinase and their implications for the design of selective inhibitors.,Brown K, Long JM, Vial SC, Dedi N, Dunster NJ, Renwick SB, Tanner AJ, Frantz JD, Fleming MA, Cheetham GM J Biol Chem. 2004 Apr 30;279(18):18727-32. Epub 2004 Feb 6. PMID:14766749[5]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
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
- ↑ Brown K, Long JM, Vial SC, Dedi N, Dunster NJ, Renwick SB, Tanner AJ, Frantz JD, Fleming MA, Cheetham GM. Crystal structures of interleukin-2 tyrosine kinase and their implications for the design of selective inhibitors. J Biol Chem. 2004 Apr 30;279(18):18727-32. Epub 2004 Feb 6. PMID:14766749 doi:10.1074/jbc.M400031200
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