4ra5 - Revision history

OCA at 06:47, 2 March 2023

2023-03-02T06:47:07Z

←Older revision		Revision as of 06:47, 2 March 2023
Line 3:		Line 3:
	<StructureSection load='4ra5' size='340' side='right'caption='[[4ra5]], [[Resolution\|resolution]] 2.61Å' scene=''>		<StructureSection load='4ra5' size='340' side='right'caption='[[4ra5]], [[Resolution\|resolution]] 2.61Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
-	<table><tr><td colspan='2'>[[4ra5]] 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=4RA5 OCA]. For a <b>guided tour on the structure components</b> use [~~http~~://~~oca~~.~~weizmann.ac.il/oca-docs~~/fgij/fg.htm?mol=4RA5 FirstGlance]. <br>	+	<table><tr><td colspan='2'>[[4ra5]] 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=4RA5 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4RA5 FirstGlance]. <br>
-	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=3L0:(1R)-9-[(1,3-DIMETHYLAZETIDIN-3-YL)(METHYL)AMINO]-1-METHYL-8-PHENYL-3,5-DIHYDRO[1,2,4]TRIAZINO[3,4-C][1,4]BENZOXAZIN-2(1H)-ONE'>3L0</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=NA:SODIUM+ION'>NA</scene>~~</td></tr>~~	+	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=3L0:(1R)-9-[(1,3-DIMETHYLAZETIDIN-3-YL)(METHYL)AMINO]-1-METHYL-8-PHENYL-3,5-DIHYDRO[1,2,4]TRIAZINO[3,4-C][1,4]BENZOXAZIN-2(1H)-ONE'>3L0</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=NA:SODIUM+ION'>NA</scene>, <scene name='pdbligand=SEP:PHOSPHOSERINE'>SEP</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='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=4ra5 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4ra5 OCA], [https://pdbe.org/4ra5 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4ra5 RCSB], [https://www.ebi.ac.uk/pdbsum/4ra5 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4ra5 ProSAT]</span></td></tr>
-	~~<tr id='related'><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat">[[4q9s\|4q9s]], [[4q9z\|4q9z]], [[4ra4\|4ra4]]</td></tr>~~	+
-	<tr id='gene'><td class="sblockLbl"><b>[[Gene\|Gene:]]</b></td><td class="sblockDat">PRKCQ, PRKCT ([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/Protein_kinase_C Protein kinase C], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.11.13 2.7.11.13] </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=4ra5 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4ra5 OCA], [~~http~~://pdbe.org/4ra5 PDBe], [~~http~~://www.rcsb.org/pdb/explore.do?structureId=4ra5 RCSB], [~~http~~://www.ebi.ac.uk/pdbsum/4ra5 PDBsum], [~~http~~://prosat.h-its.org/prosat/prosatexe?pdbcode=4ra5 ProSAT]</span></td></tr>	+
	</table>		</table>
	== Function ==		== Function ==
-	[~~[http~~://www.uniprot.org/uniprot/KPCT_HUMAN KPCT_HUMAN]] Calcium-independent, phospholipid- and diacylglycerol (DAG)-dependent serine/threonine-protein kinase that mediates non-redundant functions in T-cell receptor (TCR) signaling, including T-cells activation, proliferation, differentiation and survival, by mediating activation of multiple transcription factors such as NF-kappa-B, JUN, NFATC1 and NFATC2. In TCR-CD3/CD28-co-stimulated T-cells, is required for the activation of NF-kappa-B and JUN, which in turn are essential for IL2 production, and participates to the calcium-dependent NFATC1 and NFATC2 transactivation. Mediates the activation of the canonical NF-kappa-B pathway (NFKB1) by direct phosphorylation of CARD11 on several serine residues, inducing CARD11 association with lipid rafts and recruitment of the BCL10-MALT1 complex, which then activates IKK complex, resulting in nuclear translocation and activation of NFKB1. May also play an indirect role in activation of the non-canonical NF-kappa-B (NFKB2) pathway. In the signaling pathway leading to JUN activation, acts by phosphorylating the mediator STK39/SPAK and may not act through MAP kinases signaling. Plays a critical role in TCR/CD28-induced NFATC1 and NFATC2 transactivation by participating in the regulation of reduced inositol 1,4,5-trisphosphate generation and intracellular calcium mobilization. After costimulation of T-cells through CD28 can phosphorylate CBLB and is required for the ubiquitination and subsequent degradation of CBLB, which is a prerequisite for the activation of TCR. During T-cells differentiation, plays an important role in the development of T-helper 2 (Th2) cells following immune and inflammatory responses, and, in the development of inflammatory autoimmune diseases, is necessary for the activation of IL17-producing Th17 cells. May play a minor role in Th1 response. Upon TCR stimulation, mediates T-cell protective survival signal by phosphorylating BAD, thus protecting T-cells from BAD-induced apoptosis, and by up-regulating BCL-X(L)/BCL2L1 levels through NF-kappa-B and JUN pathways. In platelets, regulates signal transduction downstream of the ITGA2B, CD36/GP4, F2R/PAR1 and F2RL3/PAR4 receptors, playing a positive role in 'outside-in' signaling and granule secretion signal transduction. May relay signals from the activated ITGA2B receptor by regulating the uncoupling of WASP and WIPF1, thereby permitting the regulation of actin filament nucleation and branching activity of the Arp2/3 complex. May mediate inhibitory effects of free fatty acids on insulin signaling by phosphorylating IRS1, which in turn blocks IRS1 tyrosine phosphorylation and downstream activation of the PI3K/AKT pathway. Phosphorylates MSN (moesin) in the presence of phosphatidylglycerol or phosphatidylinositol. Phosphorylates PDPK1 at 'Ser-504' and 'Ser-532' and negatively regulates its ability to phosphorylate PKB/AKT1.<ref>PMID:8657160</ref> <ref>PMID:11342610</ref> <ref>PMID:14988727</ref> <ref>PMID:15364919</ref> <ref>PMID:16252004</ref> <ref>PMID:16356855</ref> <ref>PMID:16709830</ref> <ref>PMID:19549985</ref>	+	[https://www.uniprot.org/uniprot/KPCT_HUMAN KPCT_HUMAN] Calcium-independent, phospholipid- and diacylglycerol (DAG)-dependent serine/threonine-protein kinase that mediates non-redundant functions in T-cell receptor (TCR) signaling, including T-cells activation, proliferation, differentiation and survival, by mediating activation of multiple transcription factors such as NF-kappa-B, JUN, NFATC1 and NFATC2. In TCR-CD3/CD28-co-stimulated T-cells, is required for the activation of NF-kappa-B and JUN, which in turn are essential for IL2 production, and participates to the calcium-dependent NFATC1 and NFATC2 transactivation. Mediates the activation of the canonical NF-kappa-B pathway (NFKB1) by direct phosphorylation of CARD11 on several serine residues, inducing CARD11 association with lipid rafts and recruitment of the BCL10-MALT1 complex, which then activates IKK complex, resulting in nuclear translocation and activation of NFKB1. May also play an indirect role in activation of the non-canonical NF-kappa-B (NFKB2) pathway. In the signaling pathway leading to JUN activation, acts by phosphorylating the mediator STK39/SPAK and may not act through MAP kinases signaling. Plays a critical role in TCR/CD28-induced NFATC1 and NFATC2 transactivation by participating in the regulation of reduced inositol 1,4,5-trisphosphate generation and intracellular calcium mobilization. After costimulation of T-cells through CD28 can phosphorylate CBLB and is required for the ubiquitination and subsequent degradation of CBLB, which is a prerequisite for the activation of TCR. During T-cells differentiation, plays an important role in the development of T-helper 2 (Th2) cells following immune and inflammatory responses, and, in the development of inflammatory autoimmune diseases, is necessary for the activation of IL17-producing Th17 cells. May play a minor role in Th1 response. Upon TCR stimulation, mediates T-cell protective survival signal by phosphorylating BAD, thus protecting T-cells from BAD-induced apoptosis, and by up-regulating BCL-X(L)/BCL2L1 levels through NF-kappa-B and JUN pathways. In platelets, regulates signal transduction downstream of the ITGA2B, CD36/GP4, F2R/PAR1 and F2RL3/PAR4 receptors, playing a positive role in 'outside-in' signaling and granule secretion signal transduction. May relay signals from the activated ITGA2B receptor by regulating the uncoupling of WASP and WIPF1, thereby permitting the regulation of actin filament nucleation and branching activity of the Arp2/3 complex. May mediate inhibitory effects of free fatty acids on insulin signaling by phosphorylating IRS1, which in turn blocks IRS1 tyrosine phosphorylation and downstream activation of the PI3K/AKT pathway. Phosphorylates MSN (moesin) in the presence of phosphatidylglycerol or phosphatidylinositol. Phosphorylates PDPK1 at 'Ser-504' and 'Ser-532' and negatively regulates its ability to phosphorylate PKB/AKT1.<ref>PMID:8657160</ref> <ref>PMID:11342610</ref> <ref>PMID:14988727</ref> <ref>PMID:15364919</ref> <ref>PMID:16252004</ref> <ref>PMID:16356855</ref> <ref>PMID:16709830</ref> <ref>PMID:19549985</ref>
	<div style="background-color:#fffaf0;">		<div style="background-color:#fffaf0;">
	== Publication Abstract from PubMed ==		== Publication Abstract from PubMed ==
Line 24:		Line 20:

	==See Also==		==See Also==
-	*[[Protein kinase C\|Protein kinase C]]	+	*[[Protein kinase C 3D structures\|Protein kinase C 3D structures]]
	== References ==		== References ==
	<references/>		<references/>
	__TOC__		__TOC__
	</StructureSection>		</StructureSection>
-	[[Category: ~~Human~~]]	+	[[Category: Homo sapiens]]
	[[Category: Large Structures]]		[[Category: Large Structures]]
-	~~[[Category: Protein kinase C]]~~	+	[[Category: Argiriadi MA]]
-	[[Category: Argiriadi~~, M A~~]]	+	[[Category: George DM]]
-	[[Category: George~~, D M]]~~	+
-	~~[[Category: Kinase domain]]~~	+
-	~~[[Category: Pkc theta kinase]]~~	+
-	~~[[Category: Proteros biostructures gmbh]]~~	+
-	~~[[Category: Transferase-transferase inhibitor complex~~]]	+

OCA at 10:19, 1 May 2019

2019-05-01T10:19:50Z

←Older revision		Revision as of 10:19, 1 May 2019
Line 1:		Line 1:

	==Human Protein Kinase C THETA IN COMPLEX WITH LIGAND COMPOUND 11a (6-[(1,3-Dimethyl-azetidin-3-yl)-methyl-amino]-4(R)-methyl-7-phenyl-2,10-dihydro-9-oxa-1,2,4a-triaza-phenanthren-3-one)==		==Human Protein Kinase C THETA IN COMPLEX WITH LIGAND COMPOUND 11a (6-[(1,3-Dimethyl-azetidin-3-yl)-methyl-amino]-4(R)-methyl-7-phenyl-2,10-dihydro-9-oxa-1,2,4a-triaza-phenanthren-3-one)==
-	<StructureSection load='4ra5' size='340' side='right' caption='[[4ra5]], [[Resolution\|resolution]] 2.61Å' scene=''>	+	<StructureSection load='4ra5' size='340' side='right'caption='[[4ra5]], [[Resolution\|resolution]] 2.61Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
-	<table><tr><td colspan='2'>[[4ra5]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4RA5 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4RA5 FirstGlance]. <br>	+	<table><tr><td colspan='2'>[[4ra5]] 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=4RA5 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4RA5 FirstGlance]. <br>
	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=3L0:(1R)-9-[(1,3-DIMETHYLAZETIDIN-3-YL)(METHYL)AMINO]-1-METHYL-8-PHENYL-3,5-DIHYDRO[1,2,4]TRIAZINO[3,4-C][1,4]BENZOXAZIN-2(1H)-ONE'>3L0</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=NA:SODIUM+ION'>NA</scene></td></tr>		</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=3L0:(1R)-9-[(1,3-DIMETHYLAZETIDIN-3-YL)(METHYL)AMINO]-1-METHYL-8-PHENYL-3,5-DIHYDRO[1,2,4]TRIAZINO[3,4-C][1,4]BENZOXAZIN-2(1H)-ONE'>3L0</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=NA:SODIUM+ION'>NA</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='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='related'><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat">[[4q9s\|4q9s]], [[4q9z\|4q9z]], [[4ra4\|4ra4]]</td></tr>		<tr id='related'><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat">[[4q9s\|4q9s]], [[4q9z\|4q9z]], [[4ra4\|4ra4]]</td></tr>
		+	<tr id='gene'><td class="sblockLbl"><b>[[Gene\|Gene:]]</b></td><td class="sblockDat">PRKCQ, PRKCT ([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/Protein_kinase_C Protein kinase C], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.11.13 2.7.11.13] </span></td></tr>		<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Protein_kinase_C Protein kinase C], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.11.13 2.7.11.13] </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=4ra5 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4ra5 OCA], [http://pdbe.org/4ra5 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4ra5 RCSB], [http://www.ebi.ac.uk/pdbsum/4ra5 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4ra5 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=4ra5 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4ra5 OCA], [http://pdbe.org/4ra5 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4ra5 RCSB], [http://www.ebi.ac.uk/pdbsum/4ra5 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4ra5 ProSAT]</span></td></tr>
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	</div>		</div>
	<div class="pdbe-citations 4ra5" style="background-color:#fffaf0;"></div>		<div class="pdbe-citations 4ra5" style="background-color:#fffaf0;"></div>
		+
		+	==See Also==
		+	*[[Protein kinase C\|Protein kinase C]]
	== References ==		== References ==
	<references/>		<references/>
	__TOC__		__TOC__
	</StructureSection>		</StructureSection>
		+	[[Category: Human]]
		+	[[Category: Large Structures]]
	[[Category: Protein kinase C]]		[[Category: Protein kinase C]]
	[[Category: Argiriadi, M A]]		[[Category: Argiriadi, M A]]

OCA at 12:59, 11 August 2016

2016-08-11T12:59:43Z

←Older revision		Revision as of 12:59, 11 August 2016
Line 1:		Line 1:
		+
	==Human Protein Kinase C THETA IN COMPLEX WITH LIGAND COMPOUND 11a (6-[(1,3-Dimethyl-azetidin-3-yl)-methyl-amino]-4(R)-methyl-7-phenyl-2,10-dihydro-9-oxa-1,2,4a-triaza-phenanthren-3-one)==		==Human Protein Kinase C THETA IN COMPLEX WITH LIGAND COMPOUND 11a (6-[(1,3-Dimethyl-azetidin-3-yl)-methyl-amino]-4(R)-methyl-7-phenyl-2,10-dihydro-9-oxa-1,2,4a-triaza-phenanthren-3-one)==
	<StructureSection load='4ra5' size='340' side='right' caption='[[4ra5]], [[Resolution\|resolution]] 2.61Å' scene=''>		<StructureSection load='4ra5' size='340' side='right' caption='[[4ra5]], [[Resolution\|resolution]] 2.61Å' scene=''>
Line 7:		Line 8:
	<tr id='related'><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat">[[4q9s\|4q9s]], [[4q9z\|4q9z]], [[4ra4\|4ra4]]</td></tr>		<tr id='related'><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat">[[4q9s\|4q9s]], [[4q9z\|4q9z]], [[4ra4\|4ra4]]</td></tr>
	<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Protein_kinase_C Protein kinase C], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.11.13 2.7.11.13] </span></td></tr>		<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Protein_kinase_C Protein kinase C], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.11.13 2.7.11.13] </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=4ra5 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4ra5 OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4ra5 RCSB], [http://www.ebi.ac.uk/pdbsum/4ra5 PDBsum]</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=4ra5 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4ra5 OCA], [http://pdbe.org/4ra5 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4ra5 RCSB], [http://www.ebi.ac.uk/pdbsum/4ra5 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4ra5 ProSAT]</span></td></tr>
	</table>		</table>
	== Function ==		== Function ==
Line 19:		Line 20:
	From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>		From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
	</div>		</div>
		+	<div class="pdbe-citations 4ra5" style="background-color:#fffaf0;"></div>
	== References ==		== References ==
	<references/>		<references/>

OCA at 01:58, 25 December 2014

2014-12-25T01:58:43Z

←Older revision		Revision as of 01:58, 25 December 2014
Line 9:		Line 9:
	<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=4ra5 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4ra5 OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4ra5 RCSB], [http://www.ebi.ac.uk/pdbsum/4ra5 PDBsum]</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=4ra5 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4ra5 OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4ra5 RCSB], [http://www.ebi.ac.uk/pdbsum/4ra5 PDBsum]</span></td></tr>
	</table>		</table>
		+	== Function ==
		+	[[http://www.uniprot.org/uniprot/KPCT_HUMAN KPCT_HUMAN]] Calcium-independent, phospholipid- and diacylglycerol (DAG)-dependent serine/threonine-protein kinase that mediates non-redundant functions in T-cell receptor (TCR) signaling, including T-cells activation, proliferation, differentiation and survival, by mediating activation of multiple transcription factors such as NF-kappa-B, JUN, NFATC1 and NFATC2. In TCR-CD3/CD28-co-stimulated T-cells, is required for the activation of NF-kappa-B and JUN, which in turn are essential for IL2 production, and participates to the calcium-dependent NFATC1 and NFATC2 transactivation. Mediates the activation of the canonical NF-kappa-B pathway (NFKB1) by direct phosphorylation of CARD11 on several serine residues, inducing CARD11 association with lipid rafts and recruitment of the BCL10-MALT1 complex, which then activates IKK complex, resulting in nuclear translocation and activation of NFKB1. May also play an indirect role in activation of the non-canonical NF-kappa-B (NFKB2) pathway. In the signaling pathway leading to JUN activation, acts by phosphorylating the mediator STK39/SPAK and may not act through MAP kinases signaling. Plays a critical role in TCR/CD28-induced NFATC1 and NFATC2 transactivation by participating in the regulation of reduced inositol 1,4,5-trisphosphate generation and intracellular calcium mobilization. After costimulation of T-cells through CD28 can phosphorylate CBLB and is required for the ubiquitination and subsequent degradation of CBLB, which is a prerequisite for the activation of TCR. During T-cells differentiation, plays an important role in the development of T-helper 2 (Th2) cells following immune and inflammatory responses, and, in the development of inflammatory autoimmune diseases, is necessary for the activation of IL17-producing Th17 cells. May play a minor role in Th1 response. Upon TCR stimulation, mediates T-cell protective survival signal by phosphorylating BAD, thus protecting T-cells from BAD-induced apoptosis, and by up-regulating BCL-X(L)/BCL2L1 levels through NF-kappa-B and JUN pathways. In platelets, regulates signal transduction downstream of the ITGA2B, CD36/GP4, F2R/PAR1 and F2RL3/PAR4 receptors, playing a positive role in 'outside-in' signaling and granule secretion signal transduction. May relay signals from the activated ITGA2B receptor by regulating the uncoupling of WASP and WIPF1, thereby permitting the regulation of actin filament nucleation and branching activity of the Arp2/3 complex. May mediate inhibitory effects of free fatty acids on insulin signaling by phosphorylating IRS1, which in turn blocks IRS1 tyrosine phosphorylation and downstream activation of the PI3K/AKT pathway. Phosphorylates MSN (moesin) in the presence of phosphatidylglycerol or phosphatidylinositol. Phosphorylates PDPK1 at 'Ser-504' and 'Ser-532' and negatively regulates its ability to phosphorylate PKB/AKT1.<ref>PMID:8657160</ref> <ref>PMID:11342610</ref> <ref>PMID:14988727</ref> <ref>PMID:15364919</ref> <ref>PMID:16252004</ref> <ref>PMID:16356855</ref> <ref>PMID:16709830</ref> <ref>PMID:19549985</ref>
	<div style="background-color:#fffaf0;">		<div style="background-color:#fffaf0;">
	== Publication Abstract from PubMed ==		== Publication Abstract from PubMed ==
Line 22:		Line 24:
	</StructureSection>		</StructureSection>
	[[Category: Protein kinase C]]		[[Category: Protein kinase C]]
-	[[Category: Argiriadi, M A.]]	+	[[Category: Argiriadi, M A]]
-	[[Category: George, D M.]]	+	[[Category: George, D M]]
	[[Category: Kinase domain]]		[[Category: Kinase domain]]
	[[Category: Pkc theta kinase]]		[[Category: Pkc theta kinase]]
	[[Category: Proteros biostructures gmbh]]		[[Category: Proteros biostructures gmbh]]
	[[Category: Transferase-transferase inhibitor complex]]		[[Category: Transferase-transferase inhibitor complex]]

OCA at 07:41, 8 October 2014

2014-10-08T07:41:34Z

←Older revision		Revision as of 07:41, 8 October 2014
Line 1:		Line 1:
-	'''~~Unreleased~~ structure'''	+	==Human Protein Kinase C THETA IN COMPLEX WITH LIGAND COMPOUND 11a (6-[(1,3-Dimethyl-azetidin-3-yl)-methyl-amino]-4(R)-methyl-7-phenyl-2,10-dihydro-9-oxa-1,2,4a-triaza-phenanthren-3-one)==
		+	<StructureSection load='4ra5' size='340' side='right' caption='[[4ra5]], [[Resolution\|resolution]] 2.61Å' scene=''>
		+	== Structural highlights ==
		+	<table><tr><td colspan='2'>[[4ra5]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4RA5 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4RA5 FirstGlance]. <br>
		+	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=3L0:(1R)-9-[(1,3-DIMETHYLAZETIDIN-3-YL)(METHYL)AMINO]-1-METHYL-8-PHENYL-3,5-DIHYDRO[1,2,4]TRIAZINO[3,4-C][1,4]BENZOXAZIN-2(1H)-ONE'>3L0</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=NA:SODIUM+ION'>NA</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='related'><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat">[[4q9s\|4q9s]], [[4q9z\|4q9z]], [[4ra4\|4ra4]]</td></tr>
		+	<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Protein_kinase_C Protein kinase C], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.11.13 2.7.11.13] </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=4ra5 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4ra5 OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4ra5 RCSB], [http://www.ebi.ac.uk/pdbsum/4ra5 PDBsum]</span></td></tr>
		+	</table>
		+	<div style="background-color:#fffaf0;">
		+	== Publication Abstract from PubMed ==
		+	We previously demonstrated that selective inhibition of Protein Kinase C theta (PKCtheta) with triazinone 1 resulted in dose-dependent reduction of paw swelling in a mouse model of arthritis.1, 2 However, a high concentration was required for efficacy thus providing only a minimal safety window. Herein we describe a strategy to deliver safer compounds based on the hypothesis that optimizing potency in concert with good oral pharmacokinetic (PK) properties would enable in vivo efficacy at reduced exposures resulting in an improved safety window. Ultimately, transformation of 1 yielded analogues which demonstrated excellent potency and PK, and fully inhibited IL-2 production in an acute model. In spite of good exposure, twice-a-day treatment with 17l in the glucose-6-phosphate isomerase (GPI) chronic in vivo mouse model of arthritis yielded only moderate efficacy. On the basis of the exposure achieved, we conclude that PKCtheta inhibition alone is insufficient for complete efficacy in this rodent arthritis model.

-	~~The entry 4ra5 is ON HOLD until Paper Publication~~	+	Optimized Protein Kinase C theta (PKCtheta) Inhibitors Reveal Only Modest Anti-Inflammatory Efficacy in a Rodent Model of Arthritis.,George DM, Breinlinger EC, Argiriadi MA, Zhang Y, Wang J, Bansal-Pakala P, Duignan DB, Honore P, Lang Q, Mittelstadt S, Rundell L, Schwartz A, Sun J, Edmunds JJ J Med Chem. 2014 Sep 25. PMID:25254961<ref>PMID:25254961</ref>

-	~~Authors~~: Argiriadi, M.A., George, D.M.	+	From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
-		+	</div>
-	~~Description~~:	+	== References ==
		+	<references/>
		+	__TOC__
		+	</StructureSection>
		+	[[Category: Protein kinase C]]
		+	[[Category: Argiriadi, M A.]]
		+	[[Category: George, D M.]]
		+	[[Category: Kinase domain]]
		+	[[Category: Pkc theta kinase]]
		+	[[Category: Proteros biostructures gmbh]]
		+	[[Category: Transferase-transferase inhibitor complex]]

OCA: Protected "4ra5" [edit=sysop:move=sysop]

2014-09-24T08:28:05Z

Protected "4ra5" [edit=sysop:move=sysop]

←Older revision

Revision as of 08:28, 24 September 2014

OCA: New page: '''Unreleased structure''' The entry 4ra5 is ON HOLD until Paper Publication Authors: Argiriadi, M.A., George, D.M. Description:

2014-09-24T08:28:03Z

New page: '''Unreleased structure''' The entry 4ra5 is ON HOLD until Paper Publication Authors: Argiriadi, M.A., George, D.M. Description:

New page

'''Unreleased structure'''

The entry 4ra5 is ON HOLD until Paper Publication

Authors: Argiriadi, M.A., George, D.M.

Description: