4qd6: Difference between revisions

Revision as of 08:51, 24 April 2019

ITK kinase domain in complex with inhibitor compound

Structural highlights

4qd6 is a 2 chain structure with sequence from Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:	30T
Related:	4mf0, 4mf1
Gene:	ITK, EMT, LYK (HUMAN)
Activity:	Non-specific protein-tyrosine kinase, with EC number 2.7.10.2
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

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]

Publication Abstract from PubMed

Starting from benzylpyrimidine 2, molecular modeling and X-ray crystallography were used to design highly potent inhibitors of Interleukin-2 inducible T-cell kinase (ITK). Sulfonylpyridine 4i showed sub-nanomolar affinity against ITK, was selective versus Lck and its activity in the Jurkat cell-based assay was greatly improved over 2.

Design, synthesis and structure-activity relationships of a novel class of sulfonylpyridine inhibitors of Interleukin-2 inducible T-cell kinase (ITK).,Trani G, Barker JJ, Bromidge SM, Brookfield FA, Burch JD, Chen Y, Eigenbrot C, Heifetz A, Ismaili MH, Johnson A, Krulle TM, MacKinnon CH, Maghames R, McEwan PA, Montalbetti CA, Ortwine DF, Perez-Fuertes Y, Vaidya DG, Wang X, Zarrin AA, Pei Z Bioorg Med Chem Lett. 2014 Dec 15;24(24):5818-23. doi:, 10.1016/j.bmcl.2014.10.020. Epub 2014 Oct 12. PMID:25455497^[5]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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
↑ Trani G, Barker JJ, Bromidge SM, Brookfield FA, Burch JD, Chen Y, Eigenbrot C, Heifetz A, Ismaili MH, Johnson A, Krulle TM, MacKinnon CH, Maghames R, McEwan PA, Montalbetti CA, Ortwine DF, Perez-Fuertes Y, Vaidya DG, Wang X, Zarrin AA, Pei Z. Design, synthesis and structure-activity relationships of a novel class of sulfonylpyridine inhibitors of Interleukin-2 inducible T-cell kinase (ITK). Bioorg Med Chem Lett. 2014 Dec 15;24(24):5818-23. doi:, 10.1016/j.bmcl.2014.10.020. Epub 2014 Oct 12. PMID:25455497 doi:https://dx.doi.org/10.1016/j.bmcl.2014.10.020

Proteopedia Page Contributors and Editors (what is this?)

OCA

[1] 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

[2] 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

[3] 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

[4] 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

[5] Trani G, Barker JJ, Bromidge SM, Brookfield FA, Burch JD, Chen Y, Eigenbrot C, Heifetz A, Ismaili MH, Johnson A, Krulle TM, MacKinnon CH, Maghames R, McEwan PA, Montalbetti CA, Ortwine DF, Perez-Fuertes Y, Vaidya DG, Wang X, Zarrin AA, Pei Z. Design, synthesis and structure-activity relationships of a novel class of sulfonylpyridine inhibitors of Interleukin-2 inducible T-cell kinase (ITK). Bioorg Med Chem Lett. 2014 Dec 15;24(24):5818-23. doi:, 10.1016/j.bmcl.2014.10.020. Epub 2014 Oct 12. PMID:25455497 doi:https://dx.doi.org/10.1016/j.bmcl.2014.10.020

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@@ Line 1: / Line 1: @@
 ==ITK kinase domain in complex with inhibitor compound==
-<StructureSection load='4qd6' size='340' side='right' caption='[[4qd6]], [[Resolution|resolution]] 2.45&Aring;' scene=''>
+<StructureSection load='4qd6' size='340' side='right'caption='[[4qd6]], [[Resolution|resolution]] 2.45&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[4qd6]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4QD6 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4QD6 FirstGlance]. <br>
+<table><tr><td colspan='2'>[[4qd6]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4QD6 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4QD6 FirstGlance]. <br>
 </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=30T:TRANS-4-({6-[(5-PHENYL-1H-PYRAZOL-3-YL)AMINO]-4-(PHENYLSULFONYL)PYRIDIN-2-YL}AMINO)CYCLOHEXANOL'>30T</scene></td></tr>
 <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[4mf0|4mf0]], [[4mf1|4mf1]]</td></tr>
+<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">ITK, EMT, LYK ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</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=4qd6 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4qd6 OCA], [http://pdbe.org/4qd6 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4qd6 RCSB], [http://www.ebi.ac.uk/pdbsum/4qd6 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4qd6 ProSAT]</span></td></tr>
@@ Line 29: / Line 30: @@
 __TOC__
 </StructureSection>
+[[Category: Human]]
+[[Category: Large Structures]]
 [[Category: Non-specific protein-tyrosine kinase]]
 [[Category: Barker, J J]]

4qd6: Difference between revisions

Revision as of 08:51, 24 April 2019

ITK kinase domain in complex with inhibitor compound

Structural highlights

Disease

Function

Publication Abstract from PubMed

See Also

References

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