6vql: Difference between revisions

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<StructureSection load='6vql' size='340' side='right'caption='[[6vql]], [[Resolution|resolution]] 2.07&Aring;' scene=''>
<StructureSection load='6vql' size='340' side='right'caption='[[6vql]], [[Resolution|resolution]] 2.07&Aring;' scene=''>
== Structural highlights ==
== Structural highlights ==
<table><tr><td colspan='2'>[[6vql]] 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=6VQL OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6VQL FirstGlance]. <br>
<table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6VQL OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6VQL 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]] 2.069&#8491;</td></tr>
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.069&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=R7S:6-[(1,3-benzothiazol-6-yl)amino]-4-(cyclopropylamino)-N-[(2R)-2-fluoro-3-hydroxy-3-methylbutyl]pyridine-3-carboxamide'>R7S</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='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=R7S:6-[(1,3-benzothiazol-6-yl)amino]-4-(cyclopropylamino)-N-[(2R)-2-fluoro-3-hydroxy-3-methylbutyl]pyridine-3-carboxamide'>R7S</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=6vql FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6vql OCA], [https://pdbe.org/6vql PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6vql RCSB], [https://www.ebi.ac.uk/pdbsum/6vql PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6vql ProSAT]</span></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=6vql FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6vql OCA], [https://pdbe.org/6vql PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6vql RCSB], [https://www.ebi.ac.uk/pdbsum/6vql PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6vql ProSAT]</span></td></tr>
</table>
</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 is an attractive therapeutic target for the treatment of inflammatory conditions. Structure guided optimization of a nicotinamide series of inhibitors has been expanded to explore the IRAK4 front pocket. This has resulted in the identification of compounds such as 12 with improved potency and selectivity. Additionally 12 demonstrated activity in a pharmacokinetics/pharmacodynamics (PK/PD) model. Further optimization efforts led to the identification of the highly kinome selective 21, which demonstrated a robust PD effect and efficacy in a TLR7 driven model of murine psoriasis.
Optimization of Nicotinamides as Potent and Selective IRAK4 Inhibitors with Efficacy in a Murine Model of Psoriasis.,Nair S, Kumar SR, Paidi VR, Sistla R, Kantheti D, Polimera SR, Thangavel S, Mukherjee AJ, Das M, Bhide RS, Pitts WJ, Murugesan N, Dudhgoankar S, Nagar J, Subramani S, Mazumder D, Carman JA, Holloway DA, Li X, Fereshteh MP, Ruepp S, Palanisamy K, Mariappan TT, Maddi S, Saxena A, Elzinga P, Chimalakonda A, Ruan Q, Ghosh K, Bose S, Sack J, Yan C, Kiefer SE, Xie D, Newitt JA, Saravanakumar SP, Rampulla RA, Barrish JC, Carter PH, Hynes J Jr ACS Med Chem Lett. 2020 Jun 10;11(7):1402-1409. doi:, 10.1021/acsmedchemlett.0c00082. eCollection 2020 Jul 9. PMID:32676146<ref>PMID:32676146</ref>
From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 6vql" style="background-color:#fffaf0;"></div>


==See Also==
==See Also==
*[[Interleukin-1 receptor-associated kinase|Interleukin-1 receptor-associated kinase]]
*[[Interleukin-1 receptor-associated kinase|Interleukin-1 receptor-associated kinase]]
== References ==
<references/>
__TOC__
__TOC__
</StructureSection>
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Large Structures]]
[[Category: Sack JS]]
[[Category: Sack JS]]

Latest revision as of 12:15, 9 October 2024

CRYSTAL STRUCTURE OF INTERLEUKIN-1 RECEPTOR-ASSOCIATED KINASE 4 (IRAK4-WT) COMPLEX WITH A NICOTINAMIDE INHIBITORCRYSTAL STRUCTURE OF INTERLEUKIN-1 RECEPTOR-ASSOCIATED KINASE 4 (IRAK4-WT) COMPLEX WITH A NICOTINAMIDE INHIBITOR

Structural highlights

Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:X-ray diffraction, Resolution 2.069Å
Ligands:, , ,
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

See Also

6vql, resolution 2.07Å

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