OCA at 13:17, 1 February 2024

OCA — Thu, 01 Feb 2024 13:17:50 GMT

←Older revision		Revision as of 13:17, 1 February 2024
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	==IRAK4 in complex with inhibitor==		==IRAK4 in complex with inhibitor==
-	<StructureSection load='7qg2' size='340' side='right'caption='[[7qg2]]' scene=''>	+	<StructureSection load='7qg2' size='340' side='right'caption='[[7qg2]], [[Resolution\|resolution]] 3.03Å' 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=7QG2 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7QG2 FirstGlance]. <br>	+	<table><tr><td colspan='2'>[[7qg2]] 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=7QG2 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7QG2 FirstGlance]. <br>
-	</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=7qg2 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7qg2 OCA], [https://pdbe.org/7qg2 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7qg2 RCSB], [https://www.ebi.ac.uk/pdbsum/7qg2 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7qg2 ProSAT]</span></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]] 3.031Å</td></tr>
		+	<tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=B6I:6-methyl-4-[(1-methylcyclopropyl)amino]-2-[[1-(1-methylpiperidin-4-yl)pyrazol-4-yl]amino]pyrido[4,3-d]pyrimidin-5-one'>B6I</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=7qg2 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7qg2 OCA], [https://pdbe.org/7qg2 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7qg2 RCSB], [https://www.ebi.ac.uk/pdbsum/7qg2 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7qg2 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 ==
		+	In this article, we report the discovery of a series of pyrimidopyridones as inhibitors of IRAK4 kinase. From a previously disclosed 5-azaquinazoline series, we found that switching the pyridine ring for an N-substituted pyridone gave a novel hinge binding scaffold which retained potency against IRAK4. Importantly, introduction of the carbonyl established an internal hydrogen bond with the 4-NH, establishing a conformational lock and allowing truncation of the large basic substituent to a 1-methylcyclopyl group. Subsequent optimisation, facilitated by X-ray crystal structures, allowed identification of preferred substituents at both the pyridone core and pyrazole. Subsequent combinations of optimal groups allowed control of lipophilicity and identification of potent and selective inhibitors of IRAK4 with better in vitro permeability and lower clearance.
		+
		+	Identification and optimisation of a pyrimidopyridone series of IRAK4 inhibitors.,Cumming IA, Degorce SL, Aagaard A, Braybrooke EL, Davies NL, Diene CR, Eatherton AJ, Felstead HR, Groombridge SD, Lenz EM, Li Y, Nai Y, Pearson S, Robb GR, Scott JS, Steward OR, Wu C, Xue Y, Zhang L, Zhang Y Bioorg Med Chem. 2022 Jun 1;63:116729. doi: 10.1016/j.bmc.2022.116729. Epub 2022 , Apr 2. PMID:35439688<ref>PMID:35439688</ref>
		+
		+	From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
		+	</div>
		+	<div class="pdbe-citations 7qg2" style="background-color:#fffaf0;"></div>
		+
		+	==See Also==
		+	*[[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: Aagaard A]]		[[Category: Aagaard A]]

OCA at 12:48, 4 May 2022

OCA — Wed, 04 May 2022 12:48:59 GMT

←Older revision		Revision as of 12:48, 4 May 2022
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-	'''Unreleased structure'''

-	~~The entry~~ 7qg2 ~~is ON HOLD until Paper Publication~~	+	==IRAK4 in complex with inhibitor==
-		+	<StructureSection load='7qg2' size='340' side='right'caption='[[7qg2]]' scene=''>
-	~~Authors~~: ~~Xue~~, Y., ~~Aagaard~~, A., ~~Robb, G~~.R., ~~Degorce, S~~.L.	+	== Structural highlights ==
-		+	<table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7QG2 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7QG2 FirstGlance]. <br>
-	~~Description: IRAK4 in complex with inhibitor~~	+	</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=7qg2 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7qg2 OCA], [https://pdbe.org/7qg2 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7qg2 RCSB], [https://www.ebi.ac.uk/pdbsum/7qg2 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7qg2 ProSAT]</span></td></tr>
-	[[Category: ~~Unreleased~~ Structures]]	+	</table>
-	[[Category: ~~Robb, G.R~~]]	+	__TOC__
-	[[Category: ~~Aagaard, A~~]]	+	</StructureSection>
-	[[Category: ~~Degorce, S.L~~]]	+	[[Category: Large Structures]]
-	[[Category: Xue, Y]]	+	[[Category: Aagaard A]]
		+	[[Category: Degorce SL]]
		+	[[Category: Robb GR]]
		+	[[Category: Xue Y]]

OCA at 13:53, 22 December 2021

OCA — Wed, 22 Dec 2021 13:53:57 GMT

←Older revision		Revision as of 13:53, 22 December 2021
Line 1:		Line 1:
	'''Unreleased structure'''		'''Unreleased structure'''

-	The entry 7qg2 is ON HOLD	+	The entry 7qg2 is ON HOLD until Paper Publication

	Authors: Xue, Y., Aagaard, A., Robb, G.R., Degorce, S.L.		Authors: Xue, Y., Aagaard, A., Robb, G.R., Degorce, S.L.

OCA: Protected "7qg2" [edit=sysop:move=sysop]

OCA — Wed, 15 Dec 2021 15:35:19 GMT

Protected "7qg2" [edit=sysop:move=sysop]

←Older revision

Revision as of 15:35, 15 December 2021

OCA: New page: '''Unreleased structure''' The entry 7qg2 is ON HOLD Authors: Xue, Y., Aagaard, A., Robb, G.R., Degorce, S.L. Description: IRAK4 in complex with inhibitor [[Category: Unreleased Struct...

OCA — Wed, 15 Dec 2021 15:35:18 GMT

New page: '''Unreleased structure''' The entry 7qg2 is ON HOLD Authors: Xue, Y., Aagaard, A., Robb, G.R., Degorce, S.L. Description: IRAK4 in complex with inhibitor [[Category: Unreleased Struct...

New page

'''Unreleased structure'''

The entry 7qg2 is ON HOLD

Authors: Xue, Y., Aagaard, A., Robb, G.R., Degorce, S.L.

Description: IRAK4 in complex with inhibitor
[[Category: Unreleased Structures]]
[[Category: Robb, G.R]]
[[Category: Aagaard, A]]
[[Category: Degorce, S.L]]
[[Category: Xue, Y]]

7qg2 - Revision history

OCA at 13:17, 1 February 2024

OCA at 12:48, 4 May 2022

OCA at 13:53, 22 December 2021

OCA: Protected "7qg2" [edit=sysop:move=sysop]

OCA: New page: '''Unreleased structure''' The entry 7qg2 is ON HOLD Authors: Xue, Y., Aagaard, A., Robb, G.R., Degorce, S.L. Description: IRAK4 in complex with inhibitor [[Category: Unreleased Struct...