8dks - Revision history

OCA at 03:27, 8 September 2022

2022-09-08T03:27:28Z

←Older revision		Revision as of 03:27, 8 September 2022
Line 3:		Line 3:
	<StructureSection load='8dks' size='340' side='right'caption='[[8dks]], [[Resolution\|resolution]] 2.45Å' scene=''>		<StructureSection load='8dks' size='340' side='right'caption='[[8dks]], [[Resolution\|resolution]] 2.45Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
-	<table><tr><td colspan='2'>[[8dks]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=8DKS OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=8DKS FirstGlance]. <br>	+	<table><tr><td colspan='2'>[[8dks]] 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=8DKS OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=8DKS FirstGlance]. <br>
-	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=BME:BETA-MERCAPTOETHANOL'>BME</scene>, <scene name='pdbligand=SO9:(1S,2S,3R,4R)-3-({2-[3-(pyrrolidine-1-carbonyl)anilino]thieno[3,2-d]pyrimidin-4-yl}amino)bicyclo[2.2.1]hept-5-ene-2-carboxamide'>SO9</scene~~></td></tr>~~	+	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=BME:BETA-MERCAPTOETHANOL'>BME</scene>, <scene name='pdbligand=SEP:PHOSPHOSERINE'>SEP</scene>, <scene name='pdbligand=SO9:(1S,2S,3R,4R)-3-({2-[3-(pyrrolidine-1-carbonyl)anilino]thieno[3,2-d]pyrimidin-4-yl}amino)bicyclo[2.2.1]hept-5-ene-2-carboxamide'>SO9</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></td></tr>~~	+
-	<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[https://en.wikipedia.org/wiki/Non-specific_serine/threonine_protein_kinase Non-specific serine/threonine protein kinase], with EC number [https://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=8dks FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=8dks OCA], [https://pdbe.org/8dks PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=8dks RCSB], [https://www.ebi.ac.uk/pdbsum/8dks PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=8dks 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=8dks FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=8dks OCA], [https://pdbe.org/8dks PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=8dks RCSB], [https://www.ebi.ac.uk/pdbsum/8dks PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=8dks ProSAT]</span></td></tr>
	</table>		</table>
	== Disease ==		== 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>	+	[[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 ==		== 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>	+	[[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;">		<div style="background-color:#fffaf0;">
	== Publication Abstract from PubMed ==		== Publication Abstract from PubMed ==
Line 26:		Line 24:
	__TOC__		__TOC__
	</StructureSection>		</StructureSection>
		+	[[Category: Homo sapiens]]
	[[Category: Large Structures]]		[[Category: Large Structures]]
-	~~[[Category: Non-specific serine/threonine protein kinase]]~~	+	[[Category: Chen Y]]
-	[[Category: Chen, Y]]	+	[[Category: Lin N]]
-	[[Category: Lin, N]]	+
-	~~[[Category: Atp binding]]~~	+
-	~~[[Category: Irak4]]~~	+
-	~~[[Category: Kinase inhibitor]]~~	+
-	~~[[Category: Protein binding]]~~	+
-	~~[[Category: Pyrimidine]]~~	+
-	~~[[Category: Signaling protein~~]]	+

OCA at 06:49, 18 August 2022

2022-08-18T06:49:08Z

←Older revision		Revision as of 06:49, 18 August 2022
Line 1:		Line 1:

	==IRAK4 IN COMPLEX WITH COMPOUND #3==		==IRAK4 IN COMPLEX WITH COMPOUND #3==
-	<StructureSection load='8dks' size='340' side='right'caption='[[8dks]]' scene=''>	+	<StructureSection load='8dks' size='340' side='right'caption='[[8dks]], [[Resolution\|resolution]] 2.45Å' 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=8DKS OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=8DKS FirstGlance]. <br>	+	<table><tr><td colspan='2'>[[8dks]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=8DKS OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=8DKS 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=8dks FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=8dks OCA], [https://pdbe.org/8dks PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=8dks RCSB], [https://www.ebi.ac.uk/pdbsum/8dks PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=8dks 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=BME:BETA-MERCAPTOETHANOL'>BME</scene>, <scene name='pdbligand=SO9:(1S,2S,3R,4R)-3-({2-[3-(pyrrolidine-1-carbonyl)anilino]thieno[3,2-d]pyrimidin-4-yl}amino)bicyclo[2.2.1]hept-5-ene-2-carboxamide'>SO9</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></td></tr>
		+	<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[https://en.wikipedia.org/wiki/Non-specific_serine/threonine_protein_kinase Non-specific serine/threonine protein kinase], with EC number [https://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=8dks FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=8dks OCA], [https://pdbe.org/8dks PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=8dks RCSB], [https://www.ebi.ac.uk/pdbsum/8dks PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=8dks 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 ==
		+	Interleukin-1 receptor-associated kinase 4 (IRAK4) plays a critical role in transduction of IL-1R/TLR signaling which is responsible for innate immune response. From HTS campaign, bicyclic-pyrimidine compounds have been identified as potent IRAK4 inhibitors, exhibiting good potency in both IRAK4 biochemical and LPS induced IL-23 inhibition cell-based assays. The SAR efforts were focused on further improving on-target potency, reducing PAD activities of HTS hit molecule and improving in vivo PK profiles of early lead compounds. When different aromatic rings were fused to the pyrimidine core, and with various substituents at 2- or 4-position of the pyrimidine, the impact on potency and PK properties were observed and are discussed. Selected compounds were further evaluated in IL-1beta induced IL-6 inhibition acute animal model and rodent arthritis disease model, of which compounds 33 and 39 showed good efficacy in both studies.
		+
		+	Bicyclic pyrimidine compounds as potent IRAK4 inhibitors.,Chen Y, Tso K, Heckrodt TJ, Li H, Yen R, Lin N, Singh R, Taylor V, Masuda ES, Park G, Payan DG Bioorg Med Chem Lett. 2022 Jul 18:128900. doi: 10.1016/j.bmcl.2022.128900. PMID:35863718<ref>PMID:35863718</ref>
		+
		+	From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
		+	</div>
		+	<div class="pdbe-citations 8dks" style="background-color:#fffaf0;"></div>
		+	== References ==
		+	<references/>
	__TOC__		__TOC__
	</StructureSection>		</StructureSection>
	[[Category: Large Structures]]		[[Category: Large Structures]]
-	[[Category: Chen Y]]	+	[[Category: Non-specific serine/threonine protein kinase]]
-	[[Category: Lin N]]	+	[[Category: Chen, Y]]
		+	[[Category: Lin, N]]
		+	[[Category: Atp binding]]
		+	[[Category: Irak4]]
		+	[[Category: Kinase inhibitor]]
		+	[[Category: Protein binding]]
		+	[[Category: Pyrimidine]]
		+	[[Category: Signaling protein]]

OCA at 04:56, 3 August 2022

2022-08-03T04:56:18Z

←Older revision		Revision as of 04:56, 3 August 2022
Line 1:		Line 1:
-	'''Unreleased structure'''

-	~~The entry~~ 8dks ~~is ON HOLD~~	+	==IRAK4 IN COMPLEX WITH COMPOUND #3==
-		+	<StructureSection load='8dks' size='340' side='right'caption='[[8dks]]' scene=''>
-	~~Authors~~:	+	== Structural highlights ==
-		+	<table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=8DKS OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=8DKS FirstGlance]. <br>
-	~~Description~~:	+	</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=8dks FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=8dks OCA], [https://pdbe.org/8dks PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=8dks RCSB], [https://www.ebi.ac.uk/pdbsum/8dks PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=8dks ProSAT]</span></td></tr>
-	[[Category: ~~Unreleased~~ Structures]]	+	</table>
		+	__TOC__
		+	</StructureSection>
		+	[[Category: Large Structures]]
		+	[[Category: Chen Y]]
		+	[[Category: Lin N]]

OCA: Protected "8dks" [edit=sysop:move=sysop]

2022-07-13T04:17:52Z

Protected "8dks" [edit=sysop:move=sysop]

←Older revision

Revision as of 04:17, 13 July 2022

OCA: New page: '''Unreleased structure''' The entry 8dks is ON HOLD Authors: Description: Category: Unreleased Structures

2022-07-13T04:17:51Z

New page: '''Unreleased structure''' The entry 8dks is ON HOLD Authors: Description: Category: Unreleased Structures

New page

'''Unreleased structure'''

The entry 8dks is ON HOLD

Authors:

Description:
[[Category: Unreleased Structures]]