View source for 3kck


==A Novel Chemotype of Kinase Inhibitors==
<StructureSection load='3kck' size='340' side='right'caption='[[3kck]], [[Resolution|resolution]] 2.20&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[3kck]] is a 1 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=3KCK OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3KCK 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]] 2.2&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=3KC:3-CHLORO-4-(4H-3,4,7-TRIAZADIBENZO[CD,F]AZULEN-6-YL)PHENOL'>3KC</scene>, <scene name='pdbligand=PTR:O-PHOSPHOTYROSINE'>PTR</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=3kck FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3kck OCA], [https://pdbe.org/3kck PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3kck RCSB], [https://www.ebi.ac.uk/pdbsum/3kck PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3kck ProSAT]</span></td></tr>
</table>
== Disease ==
[https://www.uniprot.org/uniprot/JAK2_HUMAN JAK2_HUMAN] Note=Chromosomal aberrations involving JAK2 are found in both chronic and acute forms of eosinophilic, lymphoblastic and myeloid leukemia. Translocation t(8;9)(p22;p24) with PCM1 links the protein kinase domain of JAK2 to the major portion of PCM1. Translocation t(9;12)(p24;p13) with ETV6.  Defects in JAK2 are a cause of susceptibility to Budd-Chiari syndrome (BDCHS) [MIM:[https://omim.org/entry/600880 600880]. A syndrome caused by obstruction of hepatic venous outflow involving either the hepatic veins or the terminal segment of the inferior vena cava. Obstructions are generally caused by thrombosis and lead to hepatic congestion and ischemic necrosis. Clinical manifestations observed in the majority of patients include hepatomegaly, right upper quadrant pain and abdominal ascites. Budd-Chiari syndrome is associated with a combination of disease states including primary myeloproliferative syndromes and thrombophilia due to factor V Leiden, protein C deficiency and antithrombin III deficiency. Budd-Chiari syndrome is a rare but typical complication in patients with polycythemia vera.  Defects in JAK2 are a cause of polycythemia vera (PV) [MIM:[https://omim.org/entry/263300 263300]. A myeloproliferative disorder characterized by abnormal proliferation of all hematopoietic bone marrow elements, erythroid hyperplasia, an absolute increase in total blood volume, but also by myeloid leukocytosis, thrombocytosis and splenomegaly.<ref>PMID:15781101</ref> <ref>PMID:15793561</ref> <ref>PMID:15858187</ref> <ref>PMID:16603627</ref>   Defects in JAK2 gene may be the cause of thrombocythemia type 3 (THCYT3) [MIM:[https://omim.org/entry/614521 614521]. A myeloproliferative disorder characterized by elevated platelet levels due to sustained proliferation of megakaryocytes, and frequently lead to thrombotic and haemorrhagic complications.<ref>PMID:16325696</ref> <ref>PMID:22397670</ref>   Defects in JAK2 are a cause of myelofibrosis (MYELOF) [MIM:[https://omim.org/entry/254450 254450]. Myelofibrosis is a disorder characterized by replacement of the bone marrow by fibrous tissue, occurring in association with a myeloproliferative disorder. Clinical manifestations may include anemia, pallor, splenomegaly, hypermetabolic state, petechiae, ecchymosis, bleeding, lymphadenopathy, hepatomegaly, portal hypertension.  Defects in JAK2 are a cause of acute myelogenous leukemia (AML) [MIM:[https://omim.org/entry/601626 601626]. AML is a malignant disease in which hematopoietic precursors are arrested in an early stage of development.<ref>PMID:16247455</ref> 
== Function ==
[https://www.uniprot.org/uniprot/JAK2_HUMAN JAK2_HUMAN] Non-receptor tyrosine kinase involved in various processes such as cell growth, development, differentiation or histone modifications. Mediates essential signaling events in both innate and adaptive immunity. In the cytoplasm, plays a pivotal role in signal transduction via its association with type I receptors such as growth hormone (GHR), prolactin (PRLR), leptin (LEPR), erythropoietin (EPOR), thrombopoietin (THPO); or type II receptors including IFN-alpha, IFN-beta, IFN-gamma and multiple interleukins. Following ligand-binding to cell surface receptors, phosphorylates specific tyrosine residues on the cytoplasmic tails of the receptor, creating docking sites for STATs proteins. Subsequently, phosphorylates the STATs proteins once they are recruited to the receptor. Phosphorylated STATs then form homodimer or heterodimers and translocate to the nucleus to activate gene transcription. For example, cell stimulation with erythropoietin (EPO) during erythropoiesis leads to JAK2 autophosphorylation, activation, and its association with erythropoietin receptor (EPOR) that becomes phosphorylated in its cytoplasmic domain. Then, STAT5 (STAT5A or STAT5B) is recruited, phosphorylated and activated by JAK2. Once activated, dimerized STAT5 translocates into the nucleus and promotes the transcription of several essential genes involved in the modulation of erythropoiesis. In addition, JAK2 mediates angiotensin-2-induced ARHGEF1 phosphorylation. Plays a role in cell cycle by phosphorylating CDKN1B. Cooperates with TEC through reciprocal phosphorylation to mediate cytokine-driven activation of FOS transcription. In the nucleus, plays a key role in chromatin by specifically mediating phosphorylation of 'Tyr-41' of histone H3 (H3Y41ph), a specific tag that promotes exclusion of CBX5 (HP1 alpha) from chromatin.<ref>PMID:12023369</ref> <ref>PMID:19783980</ref> <ref>PMID:20098430</ref> <ref>PMID:21423214</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/kc/3kck_consurf.spt"</scriptWhenChecked>
    <scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview03.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/main_output.php?pdb_ID=3kck ConSurf].
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== Publication Abstract from PubMed ==
Pictet-Spengler condensation of aldehydes or alpha-keto-esters with 4-(2-anilinophenyl)-7-azaindole (11) or deazapurine (12) gave high yields of the 3,4-fused cyclic compounds. SAR studies, by varying the substituted benzaldehyde components, lead to the discovery of a series of potent JAK2 kinase inhibitors.

A novel chemotype of kinase inhibitors: Discovery of 3,4-ring fused 7-azaindoles and deazapurines as potent JAK2 inhibitors.,Wang T, Ledeboer MW, Duffy JP, Salituro FG, Pierce AC, Zuccola HJ, Block E, Shlyakter D, Hogan JK, Bennani YL Bioorg Med Chem Lett. 2010 Jan 1;20(1):153-6. Epub 2009 Nov 12. PMID:19945871<ref>PMID:19945871</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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<div class="pdbe-citations 3kck" style="background-color:#fffaf0;"></div>

==See Also==
*[[Janus kinase 3D structures|Janus kinase 3D structures]]
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Ledeboer MW]]
[[Category: Wang T]]
[[Category: Zuccola HJ]]