View source for 6uya


==Crystal structure of Compound 19 bound to IRAK4==
<StructureSection load='6uya' size='340' side='right'caption='[[6uya]], [[Resolution|resolution]] 1.74&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[6uya]] 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=6UYA OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6UYA 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]] 1.74&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=QL7:~{N}-[2-[(2~{R})-2-fluoranyl-3-methyl-3-oxidanyl-butyl]-6-morpholin-4-yl-1-oxidanylidene-3~{H}-isoindol-5-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide'>QL7</scene>, <scene name='pdbligand=SEP:PHOSPHOSERINE'>SEP</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</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=6uya FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6uya OCA], [https://pdbe.org/6uya PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6uya RCSB], [https://www.ebi.ac.uk/pdbsum/6uya PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6uya 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 kinase activity transduces signaling from multiple IL-1Rs and TLRs to regulate cytokines and chemokines implicated in inflammatory diseases. As such, there is high interest in identifying selective IRAK4 inhibitors for the treatment of these disorders. We previously reported the discovery of potent and selective dihydrobenzofuran inhibitors of IRAK4. Subsequent studies, however, showed inconsistent inhibition in disease-relevant pharmacodynamic models. Herein, we describe application of a human whole blood assay to the discovery of a series of benzolactam IRAK4 inhibitors. We identified potent molecule 19 that achieves robust in vivo inhibition of cytokines relevant to human disease.

Discovery of Potent Benzolactam IRAK4 Inhibitors with Robust in Vivo Activity.,Rajapaksa NS, Gobbi A, Drobnick J, Do S, Kolesnikov A, Liang J, Chen Y, Sujatha-Bhaskar S, Huang Z, Brightbill H, Francis R, Yu C, Choo EF, DeMent K, Ran Y, An L, Emson C, Maher J, Wai J, McKenzie BS, Lupardus PJ, Zarrin AA, Kiefer JR, Bryan MC ACS Med Chem Lett. 2019 Nov 11;11(3):327-333. doi:, 10.1021/acsmedchemlett.9b00380. eCollection 2020 Mar 12. PMID:32184965<ref>PMID:32184965</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 6uya" style="background-color:#fffaf0;"></div>

==See Also==
*[[Interleukin-1 receptor-associated kinase|Interleukin-1 receptor-associated kinase]]
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Bryan MC]]
[[Category: Do S]]
[[Category: Drobnick J]]
[[Category: Gobbi A]]
[[Category: Kiefer JR]]
[[Category: Kolesnikov A]]
[[Category: Liang J]]
[[Category: Lupardus PJ]]
[[Category: Rajapaksa NS]]
[[Category: Zarrin AA]]