9r9j
From Proteopedia
(Difference between revisions)
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| - | '''Unreleased structure''' | ||
| - | + | ==IRAK4 in complex with inhibitor== | |
| + | <StructureSection load='9r9j' size='340' side='right'caption='[[9r9j]], [[Resolution|resolution]] 2.39Å' scene=''> | ||
| + | == Structural highlights == | ||
| + | <table><tr><td colspan='2'>[[9r9j]] is a 4 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=9R9J OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=9R9J 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]] 2.39Å</td></tr> | ||
| + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=A1JDR:~{N}-[2-(3-methyl-3-oxidanyl-butyl)-6-(2-oxidanylpropan-2-yl)indazol-5-yl]-1-(2-methylpyridin-4-yl)pyrazole-3-carboxamide'>A1JDR</scene>, <scene name='pdbligand=SEP:PHOSPHOSERINE'>SEP</scene>, <scene name='pdbligand=TPO:PHOSPHOTHREONINE'>TPO</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=9r9j FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=9r9j OCA], [https://pdbe.org/9r9j PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=9r9j RCSB], [https://www.ebi.ac.uk/pdbsum/9r9j PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=9r9j ProSAT]</span></td></tr> | ||
| + | </table> | ||
| + | == Disease == | ||
| + | [https://www.uniprot.org/uniprot/IRAK4_HUMAN IRAK4_HUMAN] Defects in IRAK4 are the cause of recurrent isolated invasive pneumococcal disease type 1 (IPD1) [MIM:[https://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:[https://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 == | ||
| + | [https://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 inhibitors are of high interest as treatment for not only inflammatory and autoimmune diseases, but also in the field of oncology. Despite extensive research in the IRAK4 area and progression of several inhibitors into clinical trials, no IRAK4 inhibitor has yet reached the market. In this article, we describe the development of a highly potent and selective IRAK4 lead compound 5e, starting from Astellas AS2444697 (1a). The work includes identification of the pyrazole-pyridine substituent in compound 1g, binding towards the gatekeeper region of IRAK4, followed by a structure-guided scaffold hybridization that led to 5a. Subsequent optimization of substituents of the indazole scaffold yielded 5e, which exhibits a 10-fold improvement in IRAK4 cell potency and higher off-target selectivity compared to AS244697 (1a). | ||
| - | + | Generation of a potent & selective series of IRAK4 inhibitors based on a structure based, hybridization approach.,Terstiege I, Aagaard A, Berggren K, Bird J, Cumming IA, Groombridge SD, Hidestal L, Johannesson P, Korsgren P, Leuchowius KJ, Lundqvist S, Scott JS, Xue Y, Degorce SL Bioorg Med Chem. 2025 Jul 28;131:118333. doi: 10.1016/j.bmc.2025.118333. PMID:40972347<ref>PMID:40972347</ref> | |
| - | + | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |
| - | [[Category: | + | </div> |
| - | [[Category: Aagaard | + | <div class="pdbe-citations 9r9j" style="background-color:#fffaf0;"></div> |
| - | [[Category: Terstiege | + | == References == |
| - | [[Category: Xue | + | <references/> |
| + | __TOC__ | ||
| + | </StructureSection> | ||
| + | [[Category: Homo sapiens]] | ||
| + | [[Category: Large Structures]] | ||
| + | [[Category: Aagaard A]] | ||
| + | [[Category: Terstiege I]] | ||
| + | [[Category: Xue Y]] | ||
Current revision
IRAK4 in complex with inhibitor
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