5kx7: Difference between revisions

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-'''Unreleased structure'''
-The entry 5kx7 is ON HOLD
+==Irak4-inhibitor co-structure==
+<StructureSection load='5kx7' size='340' side='right' caption='[[5kx7]], [[Resolution|resolution]] 2.80&Aring;' scene=''>
+== Structural highlights ==
+<table><tr><td colspan='2'>[[5kx7]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5KX7 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5KX7 FirstGlance]. <br>
+</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=6YD:~{N}-(3-aminocarbonyl-1-methyl-pyrazol-4-yl)-6-(1-methylpyrazol-4-yl)pyridine-2-carboxamide'>6YD</scene></td></tr>
+<tr id='NonStdRes'><td class="sblockLbl"><b>[[Non-Standard_Residue|NonStd Res:]]</b></td><td class="sblockDat"><scene name='pdbligand=SEP:PHOSPHOSERINE'>SEP</scene>, <scene name='pdbligand=TPO:PHOSPHOTHREONINE'>TPO</scene></td></tr>
+<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[5kx8|5kx8]]</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_serine/threonine_protein_kinase Non-specific serine/threonine protein kinase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.11.1 2.7.11.1] </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=5kx7 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5kx7 OCA], [http://pdbe.org/5kx7 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5kx7 RCSB], [http://www.ebi.ac.uk/pdbsum/5kx7 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5kx7 ProSAT]</span></td></tr>
+</table>
+== Disease ==
+[[http://www.uniprot.org/uniprot/IRAK4_HUMAN IRAK4_HUMAN]] Defects in IRAK4 are the cause of recurrent isolated invasive pneumococcal disease type 1 (IPD1) [MIM:[http://omim.org/entry/610799 610799]]. Recurrent invasive pneumococcal disease (IPD) is defined as two episodes of IPD occurring at least 1 month apart, whether caused by the same or different serotypes or strains. Recurrent IPD occurs in at least 2% of patients in most series, making IPD the most important known risk factor for subsequent IPD.<ref>PMID:16950813</ref>   Defects in IRAK4 are the cause of IRAK4 deficiency (IRAK4D) [MIM:[http://omim.org/entry/607676 607676]]. IRAK4 deficiency causes extracellular pyogenic bacterial and fungal infections in otherwise healthy children.<ref>PMID:12925671</ref> <ref>PMID:12637671</ref>
+== Function ==
+[[http://www.uniprot.org/uniprot/IRAK4_HUMAN IRAK4_HUMAN]] Serine/threonine-protein kinase that plays a critical role in initiating innate immune response against foreign pathogens. Involved in Toll-like receptor (TLR) and IL-1R signaling pathways. Is rapidly recruited by MYD88 to the receptor-signaling complex upon TLR activation to form the Myddosome together with IRAK2. Phosphorylates initially IRAK1, thus stimulating the kinase activity and intensive autophosphorylation of IRAK1. Phosphorylates E3 ubiquitin ligases Pellino proteins (PELI1, PELI2 and PELI3) to promote pellino-mediated polyubiquitination of IRAK1. Then, the ubiquitin-binding domain of IKBKG/NEMO binds to polyubiquitinated IRAK1 bringing together the IRAK1-MAP3K7/TAK1-TRAF6 complex and the NEMO-IKKA-IKKB complex. In turn, MAP3K7/TAK1 activates IKKs (CHUK/IKKA and IKBKB/IKKB) leading to NF-kappa-B nuclear translocation and activation. Alternatively, phosphorylates TIRAP to promote its ubiquitination and subsequent degradation. Phosphorylates NCF1 and regulates NADPH oxidase activation after LPS stimulation suggesting a similar mechanism during microbial infections.<ref>PMID:11960013</ref> <ref>PMID:12538665</ref> <ref>PMID:15084582</ref> <ref>PMID:17217339</ref> <ref>PMID:17337443</ref> <ref>PMID:17997719</ref> <ref>PMID:20400509</ref>
+<div style="background-color:#fffaf0;">
+== Publication Abstract from PubMed ==
+IRAK4 has been identified as potential therapeutic target for inflammatory and autoimmune diseases. Herein we report the identification and initial SAR studies of a new class of pyrazole containing IRAK4 inhibitors designed to expand chemical diversity and improve off target activity of a previously identified series. These compounds maintain potent IRAK4 activity and desirable ligand efficiency. Rat clearance and a variety of off target activities were also examined, resulting in encouraging data with tractable SAR.
-Authors: Fischmann, T.O.
+Efforts towards the optimization of a bi-aryl class of potent IRAK4 inhibitors.,Hanisak J, Seganish WM, McElroy WT, Tang H, Zhang R, Tsui HC, Fischmann T, Tulshian D, Tata J, Sondey C, Devito K, Fossetta J, Garlisi CG, Lundell D, Niu X Bioorg Med Chem Lett. 2016 Sep 1;26(17):4250-5. doi: 10.1016/j.bmcl.2016.07.048. , Epub 2016 Jul 22. PMID:27476420<ref>PMID:27476420</ref>
-Description: Irak4-inhibitor co-structure
+From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
-[[Category: Unreleased Structures]]
+</div>
-[[Category: Fischmann, T.O]]
+<div class="pdbe-citations 5kx7" style="background-color:#fffaf0;"></div>
+== References ==
+<references/>
+__TOC__
+</StructureSection>
+[[Category: Non-specific serine/threonine protein kinase]]
+[[Category: Fischmann, T O]]
+[[Category: Kinase]]
+[[Category: Phosphatase]]
+[[Category: Transferase-transferase inhibitor complex]]