6thx: Difference between revisions
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==IRAK4 in complex with inhibitor== | ==IRAK4 in complex with inhibitor== | ||
<StructureSection load='6thx' size='340' side='right'caption='[[6thx]]' scene=''> | <StructureSection load='6thx' size='340' side='right'caption='[[6thx]], [[Resolution|resolution]] 1.99Å' scene=''> | ||
== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6THX OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=6THX FirstGlance]. <br> | <table><tr><td colspan='2'>[[6thx]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6THX OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=6THX FirstGlance]. <br> | ||
</td></tr><tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://proteopedia.org/fgij/fg.htm?mol=6thx FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6thx OCA], [http://pdbe.org/6thx PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6thx RCSB], [http://www.ebi.ac.uk/pdbsum/6thx PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6thx ProSAT]</span></td></tr> | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=N9Z:2-[4-[(1-methylcyclopropyl)amino]-2-[(1-methylpyrazol-4-yl)amino]pyrido[3,2-d]pyrimidin-6-yl]ethanenitrile'>N9Z</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='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">IRAK4 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</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://proteopedia.org/fgij/fg.htm?mol=6thx FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6thx OCA], [http://pdbe.org/6thx PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6thx RCSB], [http://www.ebi.ac.uk/pdbsum/6thx PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6thx ProSAT]</span></td></tr> | |||
</table> | </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 == | |||
In this article, we report our efforts towards improving in vitro human clearance in a series of 5-azaquinazolines through a series of C4 truncations and C2 expansions. Extensive DMPK studies enabled us to tackle high Aldehyde Oxidase (AO) metabolism and unexpected discrepancies in human hepatocyte and liver microsomal intrinsic clearance. Our efforts culminated with the discovery of 5-azaquinazoline 35, which also displayed exquisite selectivity for IRAK4, and showed synergistic in vitro activity against MyD88/CD79 double mutant ABC-DLBCL in combination with the covalent BTK inhibitor acalabrutinib. | |||
Improving metabolic stability and removing aldehyde oxidase liability in a 5-azaquinazoline series of IRAK4 inhibitors.,Degorce SL, Aagaard A, Anjum R, Cumming IA, Diene CR, Fallan C, Johnson T, Leuchowius KJ, Orton AL, Pearson S, Robb GR, Rosen A, Scarfe GB, Scott JS, Smith JM, Steward OR, Terstiege I, Tucker MJ, Turner P, Wilkinson SD, Wrigley GL, Xue Y Bioorg Med Chem. 2020 Oct 15;28(23):115815. doi: 10.1016/j.bmc.2020.115815. PMID:33091850<ref>PMID:33091850</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
<div class="pdbe-citations 6thx" style="background-color:#fffaf0;"></div> | |||
== References == | |||
<references/> | |||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
[[Category: Human]] | |||
[[Category: Large Structures]] | [[Category: Large Structures]] | ||
[[Category: Aagaard A]] | [[Category: Non-specific serine/threonine protein kinase]] | ||
[[Category: Degorce | [[Category: Aagaard, A]] | ||
[[Category: Xue Y]] | [[Category: Degorce, S L]] | ||
[[Category: Xue, Y]] | |||
[[Category: Cancer]] | |||
[[Category: Inhibitor]] | |||
[[Category: Irak4]] | |||
[[Category: Kinase]] | |||
[[Category: Signaling protein]] | |||