4ppa: Difference between revisions

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New page: '''Unreleased structure''' The entry 4ppa is ON HOLD until Paper Publication Authors: Eigenbrot, C., Shia, S. Description: ITK kinase domain with compound 11 (N-[1-(3-CYANOBENZYL)-1H-P...
 
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'''Unreleased structure'''


The entry 4ppa is ON HOLD  until Paper Publication
==ITK kinase domain with compound 11 (N-[1-(3-CYANOBENZYL)-1H-PYRAZOL-4-YL]-6-(1H-PYRAZOL-4-YL)-1H-INDAZOLE-3-CARBOXAMIDE)==
<StructureSection load='4ppa' size='340' side='right'caption='[[4ppa]], [[Resolution|resolution]] 2.67&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[4ppa]] 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=4PPA OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4PPA 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]] 2.67&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=2VU:N-[1-(3-CYANOBENZYL)-1H-PYRAZOL-4-YL]-6-(1H-PYRAZOL-4-YL)-1H-INDAZOLE-3-CARBOXAMIDE'>2VU</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=4ppa FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4ppa OCA], [https://pdbe.org/4ppa PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4ppa RCSB], [https://www.ebi.ac.uk/pdbsum/4ppa PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4ppa 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>
<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.


Authors: Eigenbrot, C., Shia, S.
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>


Description: ITK kinase domain with compound 11 (N-[1-(3-CYANOBENZYL)-1H-PYRAZOL-4-YL]-6-(1H-PYRAZOL-4-YL)-1H-INDAZOLE-3-CARBOXAMIDE)
From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 4ppa" 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: Eigenbrot C]]
[[Category: Shia S]]

Latest revision as of 20:20, 20 September 2023

ITK kinase domain with compound 11 (N-[1-(3-CYANOBENZYL)-1H-PYRAZOL-4-YL]-6-(1H-PYRAZOL-4-YL)-1H-INDAZOLE-3-CARBOXAMIDE)ITK kinase domain with compound 11 (N-[1-(3-CYANOBENZYL)-1H-PYRAZOL-4-YL]-6-(1H-PYRAZOL-4-YL)-1H-INDAZOLE-3-CARBOXAMIDE)

Structural highlights

4ppa 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.
Method:X-ray diffraction, Resolution 2.67Å
Ligands:
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

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[5]

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

See Also

References

  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. ↑ 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. Discovery and optimization of indazoles as potent and selective interleukin-2 inducible T cell kinase (ITK) inhibitors. 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 doi:http://dx.doi.org/10.1016/j.bmcl.2014.04.023

4ppa, resolution 2.67Å

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