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| ==Crystal structure of human IRAK1== | | ==Crystal structure of human IRAK1== |
| <StructureSection load='6bfn' size='340' side='right' caption='[[6bfn]], [[Resolution|resolution]] 2.26Å' scene=''> | | <StructureSection load='6bfn' size='340' side='right'caption='[[6bfn]], [[Resolution|resolution]] 2.26Å' scene=''> |
| == Structural highlights == | | == Structural highlights == |
| <table><tr><td colspan='2'>[[6bfn]] 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=6BFN OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6BFN FirstGlance]. <br> | | <table><tr><td colspan='2'>[[6bfn]] is a 2 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=6BFN OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6BFN FirstGlance]. <br> |
| </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=DL1:N-[2-methoxy-4-(morpholin-4-yl)phenyl]-6-(1H-pyrazol-5-yl)pyridine-2-carboxamide'>DL1</scene></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]] 2.26Å</td></tr> |
| <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">IRAK1, IRAK ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr> | | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=DL1:N-[2-methoxy-4-(morpholin-4-yl)phenyl]-6-(1H-pyrazol-5-yl)pyridine-2-carboxamide'>DL1</scene></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'>[https://proteopedia.org/fgij/fg.htm?mol=6bfn FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6bfn OCA], [https://pdbe.org/6bfn PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6bfn RCSB], [https://www.ebi.ac.uk/pdbsum/6bfn PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6bfn ProSAT]</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=6bfn FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6bfn OCA], [http://pdbe.org/6bfn PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6bfn RCSB], [http://www.ebi.ac.uk/pdbsum/6bfn PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6bfn ProSAT]</span></td></tr> | |
| </table> | | </table> |
| == Disease == | | == Disease == |
| [[http://www.uniprot.org/uniprot/IRAK1_HUMAN IRAK1_HUMAN]] Systemic lupus erythematosus;Pediatric systemic lupus erythematosus. | | [https://www.uniprot.org/uniprot/IRAK1_HUMAN IRAK1_HUMAN] Systemic lupus erythematosus;Pediatric systemic lupus erythematosus. |
| == Function == | | == Function == |
| [[http://www.uniprot.org/uniprot/IRAK1_HUMAN IRAK1_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. Association with MYD88 leads to IRAK1 phosphorylation by IRAK4 and subsequent autophosphorylation and kinase activation. 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 the interferon regulatory factor 7 (IRF7) to induce its activation and translocation to the nucleus, resulting in transcriptional activation of type I IFN genes, which drive the cell in an antiviral state. When sumoylated, translocates to the nucleus and phosphorylates STAT3.<ref>PMID:11397809</ref> <ref>PMID:12860405</ref> <ref>PMID:14684752</ref> <ref>PMID:15084582</ref> <ref>PMID:15465816</ref> <ref>PMID:15767370</ref> <ref>PMID:17997719</ref> <ref>PMID:20400509</ref> | | [https://www.uniprot.org/uniprot/IRAK1_HUMAN IRAK1_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. Association with MYD88 leads to IRAK1 phosphorylation by IRAK4 and subsequent autophosphorylation and kinase activation. 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 the interferon regulatory factor 7 (IRF7) to induce its activation and translocation to the nucleus, resulting in transcriptional activation of type I IFN genes, which drive the cell in an antiviral state. When sumoylated, translocates to the nucleus and phosphorylates STAT3.<ref>PMID:11397809</ref> <ref>PMID:12860405</ref> <ref>PMID:14684752</ref> <ref>PMID:15084582</ref> <ref>PMID:15465816</ref> <ref>PMID:15767370</ref> <ref>PMID:17997719</ref> <ref>PMID:20400509</ref> |
| <div style="background-color:#fffaf0;">
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| == Publication Abstract from PubMed ==
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| Interleukin 1 (IL-1) receptor-associated kinases (IRAKs) are serine/threonine kinases that play critical roles in initiating innate immune responses against foreign pathogens and other types of dangers through their role in Toll-like receptor (TLR) and interleukin 1 receptor (IL-1R) mediated signaling pathways. Upon ligand binding, TLRs and IL-1Rs recruit adaptor proteins, such as myeloid differentiation primary response gene 88 (MyD88), to the membrane, which in turn recruit IRAKs via the death domains in these proteins to form the Myddosome complex, leading to IRAK kinase activation. Despite their biological and clinical significance, only the IRAK4 kinase domain structure has been determined among the four IRAK family members. Here, we report the crystal structure of the human IRAK1 kinase domain in complex with a small molecule inhibitor. The structure reveals both similarities and differences between IRAK1 and IRAK4 and is suggestive of approaches to develop IRAK1- or IRAK4-specific inhibitors for potential therapeutic applications. While the IRAK4 kinase domain is capable of homodimerization in the unphosphorylated state, we found that the IRAK1 kinase domain is constitutively monomeric regardless of its phosphorylation state. Additionally, the IRAK1 kinase domain forms heterodimers with the phosphorylated, but not unphosphorylated, IRAK4 kinase domain. Collectively, these data indicate a two-step kinase activation process in which the IRAK4 kinase domain first homodimerizes in the Myddosome, leading to its trans-autophosphorylation and activation. The phosphorylated IRAK4 kinase domain then forms heterodimers with the IRAK1 kinase domain within the Myddosome, leading to its subsequent phosphorylation and activation.
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| Crystal structure of human IRAK1.,Wang L, Qiao Q, Ferrao R, Shen C, Hatcher JM, Buhrlage SJ, Gray NS, Wu H Proc Natl Acad Sci U S A. 2017 Dec 5. pii: 1714386114. doi:, 10.1073/pnas.1714386114. PMID:29208712<ref>PMID:29208712</ref>
| | ==See Also== |
| | | *[[Interleukin-1 receptor-associated kinase|Interleukin-1 receptor-associated kinase]] |
| From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
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| </div>
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| <div class="pdbe-citations 6bfn" style="background-color:#fffaf0;"></div>
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| == References == | | == References == |
| <references/> | | <references/> |
| __TOC__ | | __TOC__ |
| </StructureSection> | | </StructureSection> |
| [[Category: Human]] | | [[Category: Homo sapiens]] |
| [[Category: Non-specific serine/threonine protein kinase]] | | [[Category: Large Structures]] |
| [[Category: Qiao, Q]] | | [[Category: Qiao Q]] |
| [[Category: Wang, L]] | | [[Category: Wang L]] |
| [[Category: Wu, H]] | | [[Category: Wu H]] |
| [[Category: Transferase]]
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