3zs5 - Revision history

OCA at 10:42, 9 May 2024

OCA — Thu, 09 May 2024 10:42:48 GMT

←Older revision		Revision as of 10:42, 9 May 2024
Line 3:		Line 3:
	<StructureSection load='3zs5' size='340' side='right'caption='[[3zs5]], [[Resolution\|resolution]] 1.60Å' scene=''>		<StructureSection load='3zs5' size='340' side='right'caption='[[3zs5]], [[Resolution\|resolution]] 1.60Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
-	<table><tr><td colspan='2'>[[3zs5]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/~~Human Human~~]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3ZS5 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3ZS5 FirstGlance]. <br>	+	<table><tr><td colspan='2'>[[3zs5]] is a 1 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=3ZS5 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3ZS5 FirstGlance]. <br>
-	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=BOG:B-OCTYLGLUCOSIDE'>BOG</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=SB2:4-[5-(4-FLUORO-PHENYL)-2-(4-METHANESULFINYL-PHENYL)-3H-IMIDAZOL-4-YL]-PYRIDINE'>SB2</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]] 1.6Å</td></tr>
-	<tr id='related'><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat"><div style='overflow: auto; max-height: 3em;'>[[1a9u\|1a9u]], [[1bl6\|1bl6]], [[1bl7\|1bl7]], [[1bmk\|1bmk]], [[1di9\|1di9]], [[1ian\|1ian]], [[1kv1\|1kv1]], [[1kv2\|1kv2]], [[1m7q\|1m7q]], [[1ouk\|1ouk]], [[1ouy\|1ouy]], [[1ove\|1ove]], [[1oz1\|1oz1]], [[1r39\|1r39]], [[1r3c\|1r3c]], [[1w7h\|1w7h]], [[1w82\|1w82]], [[1w83\|1w83]], [[1w84\|1w84]], [[1wbn\|1wbn]], [[1wbo\|1wbo]], [[1wbs\|1wbs]], [[1wbt\|1wbt]], [[1wbv\|1wbv]], [[1wbw\|1wbw]], [[1wfc\|1wfc]], [[1yqj\|1yqj]], [[1zyj\|1zyj]], [[1zz2\|1zz2]], [[1zzl\|1zzl]], [[2baj\|2baj]], [[2bak\|2bak]], [[2bal\|2bal]], [[2baq\|2baq]], [[2i0h\|2i0h]], [[2y8o\|2y8o]], [[2yis\|2yis]], [[2yiw\|2yiw]], [[2yix\|2yix]], [[3zsg\|3zsg]], [[3zsh\|3zsh]], [[3zsi\|3zsi]], [[3zya\|3zya]], [[4a9y\|4a9y]], [[4aa0\|4aa0]], [[4aa4\|4aa4]], [[4aa5\|4aa5]], [[4aac\|4aac]]</div></td></tr>	+	<tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=BOG:B-OCTYLGLUCOSIDE'>BOG</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=SB2:4-[5-(4-FLUORO-PHENYL)-2-(4-METHANESULFINYL-PHENYL)-3H-IMIDAZOL-4-YL]-PYRIDINE'>SB2</scene></td></tr>
-	<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[https://en.wikipedia.org/wiki/Mitogen-activated_protein_kinase Mitogen-activated protein kinase], with EC number [https://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.11.24 2.7.11.24] </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=3zs5 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3zs5 OCA], [https://pdbe.org/3zs5 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3zs5 RCSB], [https://www.ebi.ac.uk/pdbsum/3zs5 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3zs5 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=3zs5 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3zs5 OCA], [https://pdbe.org/3zs5 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3zs5 RCSB], [https://www.ebi.ac.uk/pdbsum/3zs5 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3zs5 ProSAT]</span></td></tr>
	</table>		</table>
	== Function ==		== Function ==
-	[[https://www.uniprot.org/uniprot/MK14_HUMAN MK14_HUMAN]] Serine/threonine kinase which acts as an essential component of the MAP kinase signal transduction pathway. MAPK14 is one of the four p38 MAPKs which play an important role in the cascades of cellular responses evoked by extracellular stimuli such as proinflammatory cytokines or physical stress leading to direct activation of transcription factors. Accordingly, p38 MAPKs phosphorylate a broad range of proteins and it has been estimated that they may have approximately 200 to 300 substrates each. Some of the targets are downstream kinases which are activated through phosphorylation and further phosphorylate additional targets. RPS6KA5/MSK1 and RPS6KA4/MSK2 can directly phosphorylate and activate transcription factors such as CREB1, ATF1, the NF-kappa-B isoform RELA/NFKB3, STAT1 and STAT3, but can also phosphorylate histone H3 and the nucleosomal protein HMGN1. RPS6KA5/MSK1 and RPS6KA4/MSK2 play important roles in the rapid induction of immediate-early genes in response to stress or mitogenic stimuli, either by inducing chromatin remodeling or by recruiting the transcription machinery. On the other hand, two other kinase targets, MAPKAPK2/MK2 and MAPKAPK3/MK3, participate in the control of gene expression mostly at the post-transcriptional level, by phosphorylating ZFP36 (tristetraprolin) and ELAVL1, and by regulating EEF2K, which is important for the elongation of mRNA during translation. MKNK1/MNK1 and MKNK2/MNK2, two other kinases activated by p38 MAPKs, regulate protein synthesis by phosphorylating the initiation factor EIF4E2. MAPK14 interacts also with casein kinase II, leading to its activation through autophosphorylation and further phosphorylation of TP53/p53. In the cytoplasm, the p38 MAPK pathway is an important regulator of protein turnover. For example, CFLAR is an inhibitor of TNF-induced apoptosis whose proteasome-mediated degradation is regulated by p38 MAPK phosphorylation. In a similar way, MAPK14 phosphorylates the ubiquitin ligase SIAH2, regulating its activity towards EGLN3. MAPK14 may also inhibit the lysosomal degradation pathway of autophagy by interfering with the intracellular trafficking of the transmembrane protein ATG9. Another function of MAPK14 is to regulate the endocytosis of membrane receptors by different mechanisms that impinge on the small GTPase RAB5A. In addition, clathrin-mediated EGFR internalization induced by inflammatory cytokines and UV irradiation depends on MAPK14-mediated phosphorylation of EGFR itself as well as of RAB5A effectors. Ectodomain shedding of transmembrane proteins is regulated by p38 MAPKs as well. In response to inflammatory stimuli, p38 MAPKs phosphorylate the membrane-associated metalloprotease ADAM17. Such phosphorylation is required for ADAM17-mediated ectodomain shedding of TGF-alpha family ligands, which results in the activation of EGFR signaling and cell proliferation. Another p38 MAPK substrate is FGFR1. FGFR1 can be translocated from the extracellular space into the cytosol and nucleus of target cells, and regulates processes such as rRNA synthesis and cell growth. FGFR1 translocation requires p38 MAPK activation. In the nucleus, many transcription factors are phosphorylated and activated by p38 MAPKs in response to different stimuli. Classical examples include ATF1, ATF2, ATF6, ELK1, PTPRH, DDIT3, TP53/p53 and MEF2C and MEF2A. The p38 MAPKs are emerging as important modulators of gene expression by regulating chromatin modifiers and remodelers. The promoters of several genes involved in the inflammatory response, such as IL6, IL8 and IL12B, display a p38 MAPK-dependent enrichment of histone H3 phosphorylation on 'Ser-10' (H3S10ph) in LPS-stimulated myeloid cells. This phosphorylation enhances the accessibility of the cryptic NF-kappa-B-binding sites marking promoters for increased NF-kappa-B recruitment. Phosphorylates CDC25B and CDC25C which is required for binding to 14-3-3 proteins and leads to initiation of a G2 delay after ultraviolet radiation. Phosphorylates TIAR following DNA damage, releasing TIAR from GADD45A mRNA and preventing mRNA degradation. The p38 MAPKs may also have kinase-independent roles, which are thought to be due to the binding to targets in the absence of phosphorylation. Protein O-Glc-N-acylation catalyzed by the OGT is regulated by MAPK14, and, although OGT does not seem to be phosphorylated by MAPK14, their interaction increases upon MAPK14 activation induced by glucose deprivation. This interaction may regulate OGT activity by recruiting it to specific targets such as neurofilament H, stimulating its O-Glc-N-acylation. Required in mid-fetal development for the growth of embryo-derived blood vessels in the labyrinth layer of the placenta. Also plays an essential role in developmental and stress-induced erythropoiesis, through regulation of EPO gene expression. Isoform MXI2 activation is stimulated by mitogens and oxidative stress and only poorly phosphorylates ELK1 and ATF2. Isoform EXIP may play a role in the early onset of apoptosis. Phosphorylates S100A9 at 'Thr-113'.<ref>PMID:9687510</ref> <ref>PMID:9430721</ref> <ref>PMID:9792677</ref> <ref>PMID:9858528</ref> <ref>PMID:10330143</ref> <ref>PMID:10943842</ref> <ref>PMID:10838079</ref> <ref>PMID:10747897</ref> <ref>PMID:11154262</ref> <ref>PMID:11333986</ref> <ref>PMID:15905572</ref> <ref>PMID:16932740</ref> <ref>PMID:17003045</ref> <ref>PMID:17724032</ref> <ref>PMID:19893488</ref> <ref>PMID:20932473</ref> <ref>PMID:20188673</ref>	+	[https://www.uniprot.org/uniprot/MK14_HUMAN MK14_HUMAN] Serine/threonine kinase which acts as an essential component of the MAP kinase signal transduction pathway. MAPK14 is one of the four p38 MAPKs which play an important role in the cascades of cellular responses evoked by extracellular stimuli such as proinflammatory cytokines or physical stress leading to direct activation of transcription factors. Accordingly, p38 MAPKs phosphorylate a broad range of proteins and it has been estimated that they may have approximately 200 to 300 substrates each. Some of the targets are downstream kinases which are activated through phosphorylation and further phosphorylate additional targets. RPS6KA5/MSK1 and RPS6KA4/MSK2 can directly phosphorylate and activate transcription factors such as CREB1, ATF1, the NF-kappa-B isoform RELA/NFKB3, STAT1 and STAT3, but can also phosphorylate histone H3 and the nucleosomal protein HMGN1. RPS6KA5/MSK1 and RPS6KA4/MSK2 play important roles in the rapid induction of immediate-early genes in response to stress or mitogenic stimuli, either by inducing chromatin remodeling or by recruiting the transcription machinery. On the other hand, two other kinase targets, MAPKAPK2/MK2 and MAPKAPK3/MK3, participate in the control of gene expression mostly at the post-transcriptional level, by phosphorylating ZFP36 (tristetraprolin) and ELAVL1, and by regulating EEF2K, which is important for the elongation of mRNA during translation. MKNK1/MNK1 and MKNK2/MNK2, two other kinases activated by p38 MAPKs, regulate protein synthesis by phosphorylating the initiation factor EIF4E2. MAPK14 interacts also with casein kinase II, leading to its activation through autophosphorylation and further phosphorylation of TP53/p53. In the cytoplasm, the p38 MAPK pathway is an important regulator of protein turnover. For example, CFLAR is an inhibitor of TNF-induced apoptosis whose proteasome-mediated degradation is regulated by p38 MAPK phosphorylation. In a similar way, MAPK14 phosphorylates the ubiquitin ligase SIAH2, regulating its activity towards EGLN3. MAPK14 may also inhibit the lysosomal degradation pathway of autophagy by interfering with the intracellular trafficking of the transmembrane protein ATG9. Another function of MAPK14 is to regulate the endocytosis of membrane receptors by different mechanisms that impinge on the small GTPase RAB5A. In addition, clathrin-mediated EGFR internalization induced by inflammatory cytokines and UV irradiation depends on MAPK14-mediated phosphorylation of EGFR itself as well as of RAB5A effectors. Ectodomain shedding of transmembrane proteins is regulated by p38 MAPKs as well. In response to inflammatory stimuli, p38 MAPKs phosphorylate the membrane-associated metalloprotease ADAM17. Such phosphorylation is required for ADAM17-mediated ectodomain shedding of TGF-alpha family ligands, which results in the activation of EGFR signaling and cell proliferation. Another p38 MAPK substrate is FGFR1. FGFR1 can be translocated from the extracellular space into the cytosol and nucleus of target cells, and regulates processes such as rRNA synthesis and cell growth. FGFR1 translocation requires p38 MAPK activation. In the nucleus, many transcription factors are phosphorylated and activated by p38 MAPKs in response to different stimuli. Classical examples include ATF1, ATF2, ATF6, ELK1, PTPRH, DDIT3, TP53/p53 and MEF2C and MEF2A. The p38 MAPKs are emerging as important modulators of gene expression by regulating chromatin modifiers and remodelers. The promoters of several genes involved in the inflammatory response, such as IL6, IL8 and IL12B, display a p38 MAPK-dependent enrichment of histone H3 phosphorylation on 'Ser-10' (H3S10ph) in LPS-stimulated myeloid cells. This phosphorylation enhances the accessibility of the cryptic NF-kappa-B-binding sites marking promoters for increased NF-kappa-B recruitment. Phosphorylates CDC25B and CDC25C which is required for binding to 14-3-3 proteins and leads to initiation of a G2 delay after ultraviolet radiation. Phosphorylates TIAR following DNA damage, releasing TIAR from GADD45A mRNA and preventing mRNA degradation. The p38 MAPKs may also have kinase-independent roles, which are thought to be due to the binding to targets in the absence of phosphorylation. Protein O-Glc-N-acylation catalyzed by the OGT is regulated by MAPK14, and, although OGT does not seem to be phosphorylated by MAPK14, their interaction increases upon MAPK14 activation induced by glucose deprivation. This interaction may regulate OGT activity by recruiting it to specific targets such as neurofilament H, stimulating its O-Glc-N-acylation. Required in mid-fetal development for the growth of embryo-derived blood vessels in the labyrinth layer of the placenta. Also plays an essential role in developmental and stress-induced erythropoiesis, through regulation of EPO gene expression. Isoform MXI2 activation is stimulated by mitogens and oxidative stress and only poorly phosphorylates ELK1 and ATF2. Isoform EXIP may play a role in the early onset of apoptosis. Phosphorylates S100A9 at 'Thr-113'.<ref>PMID:9687510</ref> <ref>PMID:9430721</ref> <ref>PMID:9792677</ref> <ref>PMID:9858528</ref> <ref>PMID:10330143</ref> <ref>PMID:10943842</ref> <ref>PMID:10838079</ref> <ref>PMID:10747897</ref> <ref>PMID:11154262</ref> <ref>PMID:11333986</ref> <ref>PMID:15905572</ref> <ref>PMID:16932740</ref> <ref>PMID:17003045</ref> <ref>PMID:17724032</ref> <ref>PMID:19893488</ref> <ref>PMID:20932473</ref> <ref>PMID:20188673</ref>
	<div style="background-color:#fffaf0;">		<div style="background-color:#fffaf0;">
	== Publication Abstract from PubMed ==		== Publication Abstract from PubMed ==
Line 27:		Line 26:
	__TOC__		__TOC__
	</StructureSection>		</StructureSection>
-	[[Category: ~~Human~~]]	+	[[Category: Homo sapiens]]
	[[Category: Large Structures]]		[[Category: Large Structures]]
-	~~[[Category: Mitogen-activated protein kinase]]~~	+	[[Category: Azevedo R]]
-	[[Category: Azevedo, R]]	+	[[Category: Kazemier B]]
-	[[Category: Kazemier, B]]	+	[[Category: Oubrie A]]
-	[[Category: Oubrie, A]]	+	[[Category: Raaijmakers HCA]]
-	[[Category: Raaijmakers~~, H C.A~~]]	+	[[Category: Van Zeeland M]]
-	[[Category: Zeeland, M ~~van]]~~	+
-	~~[[Category: Sb-203580]]~~	+
-	~~[[Category: Scio-469]]~~	+
-	~~[[Category: Tak-715]]~~	+
-	~~[[Category: Transferase]]~~	+
-	~~[[Category: Vx-745~~]]	+

OCA at 07:13, 18 August 2022

OCA — Thu, 18 Aug 2022 07:13:51 GMT

←Older revision		Revision as of 07:13, 18 August 2022
Line 3:		Line 3:
	<StructureSection load='3zs5' size='340' side='right'caption='[[3zs5]], [[Resolution\|resolution]] 1.60Å' scene=''>		<StructureSection load='3zs5' size='340' side='right'caption='[[3zs5]], [[Resolution\|resolution]] 1.60Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
-	<table><tr><td colspan='2'>[[3zs5]] is a 1 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=3ZS5 OCA]. For a <b>guided tour on the structure components</b> use [~~http~~://~~oca~~.~~weizmann.ac.il/oca-docs~~/fgij/fg.htm?mol=3ZS5 FirstGlance]. <br>	+	<table><tr><td colspan='2'>[[3zs5]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3ZS5 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3ZS5 FirstGlance]. <br>
-	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=BOG:B-OCTYLGLUCOSIDE'>BOG</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=SB2:4-[5-(4-FLUORO-PHENYL)-2-(4-METHANESULFINYL-PHENYL)-3H-IMIDAZOL-4-YL]-PYRIDINE'>SB2</scene></td></tr>	+	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=BOG:B-OCTYLGLUCOSIDE'>BOG</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=SB2:4-[5-(4-FLUORO-PHENYL)-2-(4-METHANESULFINYL-PHENYL)-3H-IMIDAZOL-4-YL]-PYRIDINE'>SB2</scene></td></tr>
-	<tr id='related'><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat">[[1a9u\|1a9u]], [[1bl6\|1bl6]], [[1bl7\|1bl7]], [[1bmk\|1bmk]], [[1di9\|1di9]], [[1ian\|1ian]], [[1kv1\|1kv1]], [[1kv2\|1kv2]], [[1m7q\|1m7q]], [[1ouk\|1ouk]], [[1ouy\|1ouy]], [[1ove\|1ove]], [[1oz1\|1oz1]], [[1r39\|1r39]], [[1r3c\|1r3c]], [[1w7h\|1w7h]], [[1w82\|1w82]], [[1w83\|1w83]], [[1w84\|1w84]], [[1wbn\|1wbn]], [[1wbo\|1wbo]], [[1wbs\|1wbs]], [[1wbt\|1wbt]], [[1wbv\|1wbv]], [[1wbw\|1wbw]], [[1wfc\|1wfc]], [[1yqj\|1yqj]], [[1zyj\|1zyj]], [[1zz2\|1zz2]], [[1zzl\|1zzl]], [[2baj\|2baj]], [[2bak\|2bak]], [[2bal\|2bal]], [[2baq\|2baq]], [[2i0h\|2i0h]], [[2y8o\|2y8o]], [[2yis\|2yis]], [[2yiw\|2yiw]], [[2yix\|2yix]], [[3zsg\|3zsg]], [[3zsh\|3zsh]], [[3zsi\|3zsi]], [[3zya\|3zya]], [[4a9y\|4a9y]], [[4aa0\|4aa0]], [[4aa4\|4aa4]], [[4aa5\|4aa5]], [[4aac\|4aac]]</td></tr>	+	<tr id='related'><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat"><div style='overflow: auto; max-height: 3em;'>[[1a9u\|1a9u]], [[1bl6\|1bl6]], [[1bl7\|1bl7]], [[1bmk\|1bmk]], [[1di9\|1di9]], [[1ian\|1ian]], [[1kv1\|1kv1]], [[1kv2\|1kv2]], [[1m7q\|1m7q]], [[1ouk\|1ouk]], [[1ouy\|1ouy]], [[1ove\|1ove]], [[1oz1\|1oz1]], [[1r39\|1r39]], [[1r3c\|1r3c]], [[1w7h\|1w7h]], [[1w82\|1w82]], [[1w83\|1w83]], [[1w84\|1w84]], [[1wbn\|1wbn]], [[1wbo\|1wbo]], [[1wbs\|1wbs]], [[1wbt\|1wbt]], [[1wbv\|1wbv]], [[1wbw\|1wbw]], [[1wfc\|1wfc]], [[1yqj\|1yqj]], [[1zyj\|1zyj]], [[1zz2\|1zz2]], [[1zzl\|1zzl]], [[2baj\|2baj]], [[2bak\|2bak]], [[2bal\|2bal]], [[2baq\|2baq]], [[2i0h\|2i0h]], [[2y8o\|2y8o]], [[2yis\|2yis]], [[2yiw\|2yiw]], [[2yix\|2yix]], [[3zsg\|3zsg]], [[3zsh\|3zsh]], [[3zsi\|3zsi]], [[3zya\|3zya]], [[4a9y\|4a9y]], [[4aa0\|4aa0]], [[4aa4\|4aa4]], [[4aa5\|4aa5]], [[4aac\|4aac]]</div></td></tr>
-	<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[~~http~~://en.wikipedia.org/wiki/Mitogen-activated_protein_kinase Mitogen-activated protein kinase], with EC number [~~http~~://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.11.24 2.7.11.24] </span></td></tr>	+	<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[https://en.wikipedia.org/wiki/Mitogen-activated_protein_kinase Mitogen-activated protein kinase], with EC number [https://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.11.24 2.7.11.24] </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=3zs5 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3zs5 OCA], [~~http~~://pdbe.org/3zs5 PDBe], [~~http~~://www.rcsb.org/pdb/explore.do?structureId=3zs5 RCSB], [~~http~~://www.ebi.ac.uk/pdbsum/3zs5 PDBsum], [~~http~~://prosat.h-its.org/prosat/prosatexe?pdbcode=3zs5 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=3zs5 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3zs5 OCA], [https://pdbe.org/3zs5 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3zs5 RCSB], [https://www.ebi.ac.uk/pdbsum/3zs5 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3zs5 ProSAT]</span></td></tr>
	</table>		</table>
	== Function ==		== Function ==
-	[[~~http~~://www.uniprot.org/uniprot/MK14_HUMAN MK14_HUMAN]] Serine/threonine kinase which acts as an essential component of the MAP kinase signal transduction pathway. MAPK14 is one of the four p38 MAPKs which play an important role in the cascades of cellular responses evoked by extracellular stimuli such as proinflammatory cytokines or physical stress leading to direct activation of transcription factors. Accordingly, p38 MAPKs phosphorylate a broad range of proteins and it has been estimated that they may have approximately 200 to 300 substrates each. Some of the targets are downstream kinases which are activated through phosphorylation and further phosphorylate additional targets. RPS6KA5/MSK1 and RPS6KA4/MSK2 can directly phosphorylate and activate transcription factors such as CREB1, ATF1, the NF-kappa-B isoform RELA/NFKB3, STAT1 and STAT3, but can also phosphorylate histone H3 and the nucleosomal protein HMGN1. RPS6KA5/MSK1 and RPS6KA4/MSK2 play important roles in the rapid induction of immediate-early genes in response to stress or mitogenic stimuli, either by inducing chromatin remodeling or by recruiting the transcription machinery. On the other hand, two other kinase targets, MAPKAPK2/MK2 and MAPKAPK3/MK3, participate in the control of gene expression mostly at the post-transcriptional level, by phosphorylating ZFP36 (tristetraprolin) and ELAVL1, and by regulating EEF2K, which is important for the elongation of mRNA during translation. MKNK1/MNK1 and MKNK2/MNK2, two other kinases activated by p38 MAPKs, regulate protein synthesis by phosphorylating the initiation factor EIF4E2. MAPK14 interacts also with casein kinase II, leading to its activation through autophosphorylation and further phosphorylation of TP53/p53. In the cytoplasm, the p38 MAPK pathway is an important regulator of protein turnover. For example, CFLAR is an inhibitor of TNF-induced apoptosis whose proteasome-mediated degradation is regulated by p38 MAPK phosphorylation. In a similar way, MAPK14 phosphorylates the ubiquitin ligase SIAH2, regulating its activity towards EGLN3. MAPK14 may also inhibit the lysosomal degradation pathway of autophagy by interfering with the intracellular trafficking of the transmembrane protein ATG9. Another function of MAPK14 is to regulate the endocytosis of membrane receptors by different mechanisms that impinge on the small GTPase RAB5A. In addition, clathrin-mediated EGFR internalization induced by inflammatory cytokines and UV irradiation depends on MAPK14-mediated phosphorylation of EGFR itself as well as of RAB5A effectors. Ectodomain shedding of transmembrane proteins is regulated by p38 MAPKs as well. In response to inflammatory stimuli, p38 MAPKs phosphorylate the membrane-associated metalloprotease ADAM17. Such phosphorylation is required for ADAM17-mediated ectodomain shedding of TGF-alpha family ligands, which results in the activation of EGFR signaling and cell proliferation. Another p38 MAPK substrate is FGFR1. FGFR1 can be translocated from the extracellular space into the cytosol and nucleus of target cells, and regulates processes such as rRNA synthesis and cell growth. FGFR1 translocation requires p38 MAPK activation. In the nucleus, many transcription factors are phosphorylated and activated by p38 MAPKs in response to different stimuli. Classical examples include ATF1, ATF2, ATF6, ELK1, PTPRH, DDIT3, TP53/p53 and MEF2C and MEF2A. The p38 MAPKs are emerging as important modulators of gene expression by regulating chromatin modifiers and remodelers. The promoters of several genes involved in the inflammatory response, such as IL6, IL8 and IL12B, display a p38 MAPK-dependent enrichment of histone H3 phosphorylation on 'Ser-10' (H3S10ph) in LPS-stimulated myeloid cells. This phosphorylation enhances the accessibility of the cryptic NF-kappa-B-binding sites marking promoters for increased NF-kappa-B recruitment. Phosphorylates CDC25B and CDC25C which is required for binding to 14-3-3 proteins and leads to initiation of a G2 delay after ultraviolet radiation. Phosphorylates TIAR following DNA damage, releasing TIAR from GADD45A mRNA and preventing mRNA degradation. The p38 MAPKs may also have kinase-independent roles, which are thought to be due to the binding to targets in the absence of phosphorylation. Protein O-Glc-N-acylation catalyzed by the OGT is regulated by MAPK14, and, although OGT does not seem to be phosphorylated by MAPK14, their interaction increases upon MAPK14 activation induced by glucose deprivation. This interaction may regulate OGT activity by recruiting it to specific targets such as neurofilament H, stimulating its O-Glc-N-acylation. Required in mid-fetal development for the growth of embryo-derived blood vessels in the labyrinth layer of the placenta. Also plays an essential role in developmental and stress-induced erythropoiesis, through regulation of EPO gene expression. Isoform MXI2 activation is stimulated by mitogens and oxidative stress and only poorly phosphorylates ELK1 and ATF2. Isoform EXIP may play a role in the early onset of apoptosis. Phosphorylates S100A9 at 'Thr-113'.<ref>PMID:9687510</ref> <ref>PMID:9430721</ref> <ref>PMID:9792677</ref> <ref>PMID:9858528</ref> <ref>PMID:10330143</ref> <ref>PMID:10943842</ref> <ref>PMID:10838079</ref> <ref>PMID:10747897</ref> <ref>PMID:11154262</ref> <ref>PMID:11333986</ref> <ref>PMID:15905572</ref> <ref>PMID:16932740</ref> <ref>PMID:17003045</ref> <ref>PMID:17724032</ref> <ref>PMID:19893488</ref> <ref>PMID:20932473</ref> <ref>PMID:20188673</ref>	+	[[https://www.uniprot.org/uniprot/MK14_HUMAN MK14_HUMAN]] Serine/threonine kinase which acts as an essential component of the MAP kinase signal transduction pathway. MAPK14 is one of the four p38 MAPKs which play an important role in the cascades of cellular responses evoked by extracellular stimuli such as proinflammatory cytokines or physical stress leading to direct activation of transcription factors. Accordingly, p38 MAPKs phosphorylate a broad range of proteins and it has been estimated that they may have approximately 200 to 300 substrates each. Some of the targets are downstream kinases which are activated through phosphorylation and further phosphorylate additional targets. RPS6KA5/MSK1 and RPS6KA4/MSK2 can directly phosphorylate and activate transcription factors such as CREB1, ATF1, the NF-kappa-B isoform RELA/NFKB3, STAT1 and STAT3, but can also phosphorylate histone H3 and the nucleosomal protein HMGN1. RPS6KA5/MSK1 and RPS6KA4/MSK2 play important roles in the rapid induction of immediate-early genes in response to stress or mitogenic stimuli, either by inducing chromatin remodeling or by recruiting the transcription machinery. On the other hand, two other kinase targets, MAPKAPK2/MK2 and MAPKAPK3/MK3, participate in the control of gene expression mostly at the post-transcriptional level, by phosphorylating ZFP36 (tristetraprolin) and ELAVL1, and by regulating EEF2K, which is important for the elongation of mRNA during translation. MKNK1/MNK1 and MKNK2/MNK2, two other kinases activated by p38 MAPKs, regulate protein synthesis by phosphorylating the initiation factor EIF4E2. MAPK14 interacts also with casein kinase II, leading to its activation through autophosphorylation and further phosphorylation of TP53/p53. In the cytoplasm, the p38 MAPK pathway is an important regulator of protein turnover. For example, CFLAR is an inhibitor of TNF-induced apoptosis whose proteasome-mediated degradation is regulated by p38 MAPK phosphorylation. In a similar way, MAPK14 phosphorylates the ubiquitin ligase SIAH2, regulating its activity towards EGLN3. MAPK14 may also inhibit the lysosomal degradation pathway of autophagy by interfering with the intracellular trafficking of the transmembrane protein ATG9. Another function of MAPK14 is to regulate the endocytosis of membrane receptors by different mechanisms that impinge on the small GTPase RAB5A. In addition, clathrin-mediated EGFR internalization induced by inflammatory cytokines and UV irradiation depends on MAPK14-mediated phosphorylation of EGFR itself as well as of RAB5A effectors. Ectodomain shedding of transmembrane proteins is regulated by p38 MAPKs as well. In response to inflammatory stimuli, p38 MAPKs phosphorylate the membrane-associated metalloprotease ADAM17. Such phosphorylation is required for ADAM17-mediated ectodomain shedding of TGF-alpha family ligands, which results in the activation of EGFR signaling and cell proliferation. Another p38 MAPK substrate is FGFR1. FGFR1 can be translocated from the extracellular space into the cytosol and nucleus of target cells, and regulates processes such as rRNA synthesis and cell growth. FGFR1 translocation requires p38 MAPK activation. In the nucleus, many transcription factors are phosphorylated and activated by p38 MAPKs in response to different stimuli. Classical examples include ATF1, ATF2, ATF6, ELK1, PTPRH, DDIT3, TP53/p53 and MEF2C and MEF2A. The p38 MAPKs are emerging as important modulators of gene expression by regulating chromatin modifiers and remodelers. The promoters of several genes involved in the inflammatory response, such as IL6, IL8 and IL12B, display a p38 MAPK-dependent enrichment of histone H3 phosphorylation on 'Ser-10' (H3S10ph) in LPS-stimulated myeloid cells. This phosphorylation enhances the accessibility of the cryptic NF-kappa-B-binding sites marking promoters for increased NF-kappa-B recruitment. Phosphorylates CDC25B and CDC25C which is required for binding to 14-3-3 proteins and leads to initiation of a G2 delay after ultraviolet radiation. Phosphorylates TIAR following DNA damage, releasing TIAR from GADD45A mRNA and preventing mRNA degradation. The p38 MAPKs may also have kinase-independent roles, which are thought to be due to the binding to targets in the absence of phosphorylation. Protein O-Glc-N-acylation catalyzed by the OGT is regulated by MAPK14, and, although OGT does not seem to be phosphorylated by MAPK14, their interaction increases upon MAPK14 activation induced by glucose deprivation. This interaction may regulate OGT activity by recruiting it to specific targets such as neurofilament H, stimulating its O-Glc-N-acylation. Required in mid-fetal development for the growth of embryo-derived blood vessels in the labyrinth layer of the placenta. Also plays an essential role in developmental and stress-induced erythropoiesis, through regulation of EPO gene expression. Isoform MXI2 activation is stimulated by mitogens and oxidative stress and only poorly phosphorylates ELK1 and ATF2. Isoform EXIP may play a role in the early onset of apoptosis. Phosphorylates S100A9 at 'Thr-113'.<ref>PMID:9687510</ref> <ref>PMID:9430721</ref> <ref>PMID:9792677</ref> <ref>PMID:9858528</ref> <ref>PMID:10330143</ref> <ref>PMID:10943842</ref> <ref>PMID:10838079</ref> <ref>PMID:10747897</ref> <ref>PMID:11154262</ref> <ref>PMID:11333986</ref> <ref>PMID:15905572</ref> <ref>PMID:16932740</ref> <ref>PMID:17003045</ref> <ref>PMID:17724032</ref> <ref>PMID:19893488</ref> <ref>PMID:20932473</ref> <ref>PMID:20188673</ref>
	<div style="background-color:#fffaf0;">		<div style="background-color:#fffaf0;">
	== Publication Abstract from PubMed ==		== Publication Abstract from PubMed ==
Line 22:		Line 22:

	==See Also==		==See Also==
-	*[[Mitogen-activated protein kinase\|Mitogen-activated protein kinase]]	+	*[[Mitogen-activated protein kinase 3D structures\|Mitogen-activated protein kinase 3D structures]]
	== References ==		== References ==
	<references/>		<references/>

OCA at 12:31, 10 May 2019

OCA — Fri, 10 May 2019 12:31:35 GMT

←Older revision		Revision as of 12:31, 10 May 2019
Line 1:		Line 1:

	==Structural basis for kinase selectivity of three clinical p38alpha inhibitors==		==Structural basis for kinase selectivity of three clinical p38alpha inhibitors==
-	<StructureSection load='3zs5' size='340' side='right' caption='[[3zs5]], [[Resolution\|resolution]] 1.60Å' scene=''>	+	<StructureSection load='3zs5' size='340' side='right'caption='[[3zs5]], [[Resolution\|resolution]] 1.60Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
	<table><tr><td colspan='2'>[[3zs5]] is a 1 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=3ZS5 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3ZS5 FirstGlance]. <br>		<table><tr><td colspan='2'>[[3zs5]] is a 1 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=3ZS5 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3ZS5 FirstGlance]. <br>
Line 20:		Line 20:
	</div>		</div>
	<div class="pdbe-citations 3zs5" style="background-color:#fffaf0;"></div>		<div class="pdbe-citations 3zs5" style="background-color:#fffaf0;"></div>
		+
		+	==See Also==
		+	*[[Mitogen-activated protein kinase\|Mitogen-activated protein kinase]]
	== References ==		== References ==
	<references/>		<references/>
Line 25:		Line 28:
	</StructureSection>		</StructureSection>
	[[Category: Human]]		[[Category: Human]]
		+	[[Category: Large Structures]]
	[[Category: Mitogen-activated protein kinase]]		[[Category: Mitogen-activated protein kinase]]
	[[Category: Azevedo, R]]		[[Category: Azevedo, R]]

OCA at 06:33, 7 February 2018

OCA — Wed, 07 Feb 2018 06:33:23 GMT

←Older revision		Revision as of 06:33, 7 February 2018
Line 20:		Line 20:
	</div>		</div>
	<div class="pdbe-citations 3zs5" style="background-color:#fffaf0;"></div>		<div class="pdbe-citations 3zs5" style="background-color:#fffaf0;"></div>
-
-	==See Also==
-	*[[Mitogen-activated protein kinase\|Mitogen-activated protein kinase]]
	== References ==		== References ==
	<references/>		<references/>
Line 33:		Line 30:
	[[Category: Oubrie, A]]		[[Category: Oubrie, A]]
	[[Category: Raaijmakers, H C.A]]		[[Category: Raaijmakers, H C.A]]
-	[[Category: Zeeland, M ~~Van~~]]	+	[[Category: Zeeland, M van]]
	[[Category: Sb-203580]]		[[Category: Sb-203580]]
	[[Category: Scio-469]]		[[Category: Scio-469]]

OCA at 19:49, 5 August 2016

OCA — Fri, 05 Aug 2016 19:49:31 GMT

←Older revision		Revision as of 19:49, 5 August 2016
Line 1:		Line 1:
		+
	==Structural basis for kinase selectivity of three clinical p38alpha inhibitors==		==Structural basis for kinase selectivity of three clinical p38alpha inhibitors==
	<StructureSection load='3zs5' size='340' side='right' caption='[[3zs5]], [[Resolution\|resolution]] 1.60Å' scene=''>		<StructureSection load='3zs5' size='340' side='right' caption='[[3zs5]], [[Resolution\|resolution]] 1.60Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
-	<table><tr><td colspan='2'>[[3zs5]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/~~Homo_sapiens Homo sapiens~~]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3ZS5 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3ZS5 FirstGlance]. <br>	+	<table><tr><td colspan='2'>[[3zs5]] is a 1 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=3ZS5 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3ZS5 FirstGlance]. <br>
	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=BOG:B-OCTYLGLUCOSIDE'>BOG</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=SB2:4-[5-(4-FLUORO-PHENYL)-2-(4-METHANESULFINYL-PHENYL)-3H-IMIDAZOL-4-YL]-PYRIDINE'>SB2</scene></td></tr>		</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=BOG:B-OCTYLGLUCOSIDE'>BOG</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=SB2:4-[5-(4-FLUORO-PHENYL)-2-(4-METHANESULFINYL-PHENYL)-3H-IMIDAZOL-4-YL]-PYRIDINE'>SB2</scene></td></tr>
	<tr id='related'><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat">[[1a9u\|1a9u]], [[1bl6\|1bl6]], [[1bl7\|1bl7]], [[1bmk\|1bmk]], [[1di9\|1di9]], [[1ian\|1ian]], [[1kv1\|1kv1]], [[1kv2\|1kv2]], [[1m7q\|1m7q]], [[1ouk\|1ouk]], [[1ouy\|1ouy]], [[1ove\|1ove]], [[1oz1\|1oz1]], [[1r39\|1r39]], [[1r3c\|1r3c]], [[1w7h\|1w7h]], [[1w82\|1w82]], [[1w83\|1w83]], [[1w84\|1w84]], [[1wbn\|1wbn]], [[1wbo\|1wbo]], [[1wbs\|1wbs]], [[1wbt\|1wbt]], [[1wbv\|1wbv]], [[1wbw\|1wbw]], [[1wfc\|1wfc]], [[1yqj\|1yqj]], [[1zyj\|1zyj]], [[1zz2\|1zz2]], [[1zzl\|1zzl]], [[2baj\|2baj]], [[2bak\|2bak]], [[2bal\|2bal]], [[2baq\|2baq]], [[2i0h\|2i0h]], [[2y8o\|2y8o]], [[2yis\|2yis]], [[2yiw\|2yiw]], [[2yix\|2yix]], [[3zsg\|3zsg]], [[3zsh\|3zsh]], [[3zsi\|3zsi]], [[3zya\|3zya]], [[4a9y\|4a9y]], [[4aa0\|4aa0]], [[4aa4\|4aa4]], [[4aa5\|4aa5]], [[4aac\|4aac]]</td></tr>		<tr id='related'><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat">[[1a9u\|1a9u]], [[1bl6\|1bl6]], [[1bl7\|1bl7]], [[1bmk\|1bmk]], [[1di9\|1di9]], [[1ian\|1ian]], [[1kv1\|1kv1]], [[1kv2\|1kv2]], [[1m7q\|1m7q]], [[1ouk\|1ouk]], [[1ouy\|1ouy]], [[1ove\|1ove]], [[1oz1\|1oz1]], [[1r39\|1r39]], [[1r3c\|1r3c]], [[1w7h\|1w7h]], [[1w82\|1w82]], [[1w83\|1w83]], [[1w84\|1w84]], [[1wbn\|1wbn]], [[1wbo\|1wbo]], [[1wbs\|1wbs]], [[1wbt\|1wbt]], [[1wbv\|1wbv]], [[1wbw\|1wbw]], [[1wfc\|1wfc]], [[1yqj\|1yqj]], [[1zyj\|1zyj]], [[1zz2\|1zz2]], [[1zzl\|1zzl]], [[2baj\|2baj]], [[2bak\|2bak]], [[2bal\|2bal]], [[2baq\|2baq]], [[2i0h\|2i0h]], [[2y8o\|2y8o]], [[2yis\|2yis]], [[2yiw\|2yiw]], [[2yix\|2yix]], [[3zsg\|3zsg]], [[3zsh\|3zsh]], [[3zsi\|3zsi]], [[3zya\|3zya]], [[4a9y\|4a9y]], [[4aa0\|4aa0]], [[4aa4\|4aa4]], [[4aa5\|4aa5]], [[4aac\|4aac]]</td></tr>
	<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Mitogen-activated_protein_kinase Mitogen-activated protein kinase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.11.24 2.7.11.24] </span></td></tr>		<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Mitogen-activated_protein_kinase Mitogen-activated protein kinase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.11.24 2.7.11.24] </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=3zs5 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3zs5 OCA], [http://www.rcsb.org/pdb/explore.do?structureId=3zs5 RCSB], [http://www.ebi.ac.uk/pdbsum/3zs5 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=3zs5 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3zs5 OCA], [http://pdbe.org/3zs5 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=3zs5 RCSB], [http://www.ebi.ac.uk/pdbsum/3zs5 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=3zs5 ProSAT]</span></td></tr>
	</table>		</table>
	== Function ==		== Function ==
Line 18:		Line 19:
	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 3zs5" style="background-color:#fffaf0;"></div>

	==See Also==		==See Also==
Line 25:		Line 27:
	__TOC__		__TOC__
	</StructureSection>		</StructureSection>
-	[[Category: ~~Homo sapiens~~]]	+	[[Category: Human]]
	[[Category: Mitogen-activated protein kinase]]		[[Category: Mitogen-activated protein kinase]]
	[[Category: Azevedo, R]]		[[Category: Azevedo, R]]

OCA at 05:21, 25 December 2014

OCA — Thu, 25 Dec 2014 05:21:04 GMT

←Older revision		Revision as of 05:21, 25 December 2014
Line 3:		Line 3:
	== Structural highlights ==		== Structural highlights ==
	<table><tr><td colspan='2'>[[3zs5]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3ZS5 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3ZS5 FirstGlance]. <br>		<table><tr><td colspan='2'>[[3zs5]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3ZS5 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3ZS5 FirstGlance]. <br>
-	</td></tr><tr><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=BOG:B-OCTYLGLUCOSIDE'>BOG</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=SB2:4-[5-(4-FLUORO-PHENYL)-2-(4-METHANESULFINYL-PHENYL)-3H-IMIDAZOL-4-YL]-PYRIDINE'>SB2</scene><br>	+	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=BOG:B-OCTYLGLUCOSIDE'>BOG</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=SB2:4-[5-(4-FLUORO-PHENYL)-2-(4-METHANESULFINYL-PHENYL)-3H-IMIDAZOL-4-YL]-PYRIDINE'>SB2</scene></td></tr>
-	<tr><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat">[[1a9u\|1a9u]], [[1bl6\|1bl6]], [[1bl7\|1bl7]], [[1bmk\|1bmk]], [[1di9\|1di9]], [[1ian\|1ian]], [[1kv1\|1kv1]], [[1kv2\|1kv2]], [[1m7q\|1m7q]], [[1ouk\|1ouk]], [[1ouy\|1ouy]], [[1ove\|1ove]], [[1oz1\|1oz1]], [[1r39\|1r39]], [[1r3c\|1r3c]], [[1w7h\|1w7h]], [[1w82\|1w82]], [[1w83\|1w83]], [[1w84\|1w84]], [[1wbn\|1wbn]], [[1wbo\|1wbo]], [[1wbs\|1wbs]], [[1wbt\|1wbt]], [[1wbv\|1wbv]], [[1wbw\|1wbw]], [[1wfc\|1wfc]], [[1yqj\|1yqj]], [[1zyj\|1zyj]], [[1zz2\|1zz2]], [[1zzl\|1zzl]], [[2baj\|2baj]], [[2bak\|2bak]], [[2bal\|2bal]], [[2baq\|2baq]], [[2i0h\|2i0h]], [[2y8o\|2y8o]], [[2yis\|2yis]], [[2yiw\|2yiw]], [[2yix\|2yix]], [[3zsg\|3zsg]], [[3zsh\|3zsh]], [[3zsi\|3zsi]], [[3zya\|3zya]], [[4a9y\|4a9y]], [[4aa0\|4aa0]], [[4aa4\|4aa4]], [[4aa5\|4aa5]], [[4aac\|4aac]]</td></tr>	+	<tr id='related'><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat">[[1a9u\|1a9u]], [[1bl6\|1bl6]], [[1bl7\|1bl7]], [[1bmk\|1bmk]], [[1di9\|1di9]], [[1ian\|1ian]], [[1kv1\|1kv1]], [[1kv2\|1kv2]], [[1m7q\|1m7q]], [[1ouk\|1ouk]], [[1ouy\|1ouy]], [[1ove\|1ove]], [[1oz1\|1oz1]], [[1r39\|1r39]], [[1r3c\|1r3c]], [[1w7h\|1w7h]], [[1w82\|1w82]], [[1w83\|1w83]], [[1w84\|1w84]], [[1wbn\|1wbn]], [[1wbo\|1wbo]], [[1wbs\|1wbs]], [[1wbt\|1wbt]], [[1wbv\|1wbv]], [[1wbw\|1wbw]], [[1wfc\|1wfc]], [[1yqj\|1yqj]], [[1zyj\|1zyj]], [[1zz2\|1zz2]], [[1zzl\|1zzl]], [[2baj\|2baj]], [[2bak\|2bak]], [[2bal\|2bal]], [[2baq\|2baq]], [[2i0h\|2i0h]], [[2y8o\|2y8o]], [[2yis\|2yis]], [[2yiw\|2yiw]], [[2yix\|2yix]], [[3zsg\|3zsg]], [[3zsh\|3zsh]], [[3zsi\|3zsi]], [[3zya\|3zya]], [[4a9y\|4a9y]], [[4aa0\|4aa0]], [[4aa4\|4aa4]], [[4aa5\|4aa5]], [[4aac\|4aac]]</td></tr>
-	<tr><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Mitogen-activated_protein_kinase Mitogen-activated protein kinase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.11.24 2.7.11.24] </span></td></tr>	+	<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Mitogen-activated_protein_kinase Mitogen-activated protein kinase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.11.24 2.7.11.24] </span></td></tr>
-	<tr><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3zs5 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3zs5 OCA], [http://www.rcsb.org/pdb/explore.do?structureId=3zs5 RCSB], [http://www.ebi.ac.uk/pdbsum/3zs5 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=3zs5 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3zs5 OCA], [http://www.rcsb.org/pdb/explore.do?structureId=3zs5 RCSB], [http://www.ebi.ac.uk/pdbsum/3zs5 PDBsum]</span></td></tr>
-	<table>	+	</table>
		+	== Function ==
		+	[[http://www.uniprot.org/uniprot/MK14_HUMAN MK14_HUMAN]] Serine/threonine kinase which acts as an essential component of the MAP kinase signal transduction pathway. MAPK14 is one of the four p38 MAPKs which play an important role in the cascades of cellular responses evoked by extracellular stimuli such as proinflammatory cytokines or physical stress leading to direct activation of transcription factors. Accordingly, p38 MAPKs phosphorylate a broad range of proteins and it has been estimated that they may have approximately 200 to 300 substrates each. Some of the targets are downstream kinases which are activated through phosphorylation and further phosphorylate additional targets. RPS6KA5/MSK1 and RPS6KA4/MSK2 can directly phosphorylate and activate transcription factors such as CREB1, ATF1, the NF-kappa-B isoform RELA/NFKB3, STAT1 and STAT3, but can also phosphorylate histone H3 and the nucleosomal protein HMGN1. RPS6KA5/MSK1 and RPS6KA4/MSK2 play important roles in the rapid induction of immediate-early genes in response to stress or mitogenic stimuli, either by inducing chromatin remodeling or by recruiting the transcription machinery. On the other hand, two other kinase targets, MAPKAPK2/MK2 and MAPKAPK3/MK3, participate in the control of gene expression mostly at the post-transcriptional level, by phosphorylating ZFP36 (tristetraprolin) and ELAVL1, and by regulating EEF2K, which is important for the elongation of mRNA during translation. MKNK1/MNK1 and MKNK2/MNK2, two other kinases activated by p38 MAPKs, regulate protein synthesis by phosphorylating the initiation factor EIF4E2. MAPK14 interacts also with casein kinase II, leading to its activation through autophosphorylation and further phosphorylation of TP53/p53. In the cytoplasm, the p38 MAPK pathway is an important regulator of protein turnover. For example, CFLAR is an inhibitor of TNF-induced apoptosis whose proteasome-mediated degradation is regulated by p38 MAPK phosphorylation. In a similar way, MAPK14 phosphorylates the ubiquitin ligase SIAH2, regulating its activity towards EGLN3. MAPK14 may also inhibit the lysosomal degradation pathway of autophagy by interfering with the intracellular trafficking of the transmembrane protein ATG9. Another function of MAPK14 is to regulate the endocytosis of membrane receptors by different mechanisms that impinge on the small GTPase RAB5A. In addition, clathrin-mediated EGFR internalization induced by inflammatory cytokines and UV irradiation depends on MAPK14-mediated phosphorylation of EGFR itself as well as of RAB5A effectors. Ectodomain shedding of transmembrane proteins is regulated by p38 MAPKs as well. In response to inflammatory stimuli, p38 MAPKs phosphorylate the membrane-associated metalloprotease ADAM17. Such phosphorylation is required for ADAM17-mediated ectodomain shedding of TGF-alpha family ligands, which results in the activation of EGFR signaling and cell proliferation. Another p38 MAPK substrate is FGFR1. FGFR1 can be translocated from the extracellular space into the cytosol and nucleus of target cells, and regulates processes such as rRNA synthesis and cell growth. FGFR1 translocation requires p38 MAPK activation. In the nucleus, many transcription factors are phosphorylated and activated by p38 MAPKs in response to different stimuli. Classical examples include ATF1, ATF2, ATF6, ELK1, PTPRH, DDIT3, TP53/p53 and MEF2C and MEF2A. The p38 MAPKs are emerging as important modulators of gene expression by regulating chromatin modifiers and remodelers. The promoters of several genes involved in the inflammatory response, such as IL6, IL8 and IL12B, display a p38 MAPK-dependent enrichment of histone H3 phosphorylation on 'Ser-10' (H3S10ph) in LPS-stimulated myeloid cells. This phosphorylation enhances the accessibility of the cryptic NF-kappa-B-binding sites marking promoters for increased NF-kappa-B recruitment. Phosphorylates CDC25B and CDC25C which is required for binding to 14-3-3 proteins and leads to initiation of a G2 delay after ultraviolet radiation. Phosphorylates TIAR following DNA damage, releasing TIAR from GADD45A mRNA and preventing mRNA degradation. The p38 MAPKs may also have kinase-independent roles, which are thought to be due to the binding to targets in the absence of phosphorylation. Protein O-Glc-N-acylation catalyzed by the OGT is regulated by MAPK14, and, although OGT does not seem to be phosphorylated by MAPK14, their interaction increases upon MAPK14 activation induced by glucose deprivation. This interaction may regulate OGT activity by recruiting it to specific targets such as neurofilament H, stimulating its O-Glc-N-acylation. Required in mid-fetal development for the growth of embryo-derived blood vessels in the labyrinth layer of the placenta. Also plays an essential role in developmental and stress-induced erythropoiesis, through regulation of EPO gene expression. Isoform MXI2 activation is stimulated by mitogens and oxidative stress and only poorly phosphorylates ELK1 and ATF2. Isoform EXIP may play a role in the early onset of apoptosis. Phosphorylates S100A9 at 'Thr-113'.<ref>PMID:9687510</ref> <ref>PMID:9430721</ref> <ref>PMID:9792677</ref> <ref>PMID:9858528</ref> <ref>PMID:10330143</ref> <ref>PMID:10943842</ref> <ref>PMID:10838079</ref> <ref>PMID:10747897</ref> <ref>PMID:11154262</ref> <ref>PMID:11333986</ref> <ref>PMID:15905572</ref> <ref>PMID:16932740</ref> <ref>PMID:17003045</ref> <ref>PMID:17724032</ref> <ref>PMID:19893488</ref> <ref>PMID:20932473</ref> <ref>PMID:20188673</ref>
	<div style="background-color:#fffaf0;">		<div style="background-color:#fffaf0;">
	== Publication Abstract from PubMed ==		== Publication Abstract from PubMed ==
Line 25:		Line 27:
	[[Category: Homo sapiens]]		[[Category: Homo sapiens]]
	[[Category: Mitogen-activated protein kinase]]		[[Category: Mitogen-activated protein kinase]]
-	[[Category: Azevedo, R.]]	+	[[Category: Azevedo, R]]
-	[[Category: Kazemier, B.]]	+	[[Category: Kazemier, B]]
-	[[Category: Oubrie, A.]]	+	[[Category: Oubrie, A]]
-	[[Category: Raaijmakers, H C.A.]]	+	[[Category: Raaijmakers, H C.A]]
-	[[Category: Zeeland, M Van.]]	+	[[Category: Zeeland, M Van]]
	[[Category: Sb-203580]]		[[Category: Sb-203580]]
	[[Category: Scio-469]]		[[Category: Scio-469]]

OCA at 09:15, 11 June 2014

OCA — Wed, 11 Jun 2014 09:15:24 GMT

←Older revision		Revision as of 09:15, 11 June 2014
Line 1:		Line 1:
-	[[~~Image:~~3zs5.~~png~~\|~~left~~\|~~200px~~]]	+	==Structural basis for kinase selectivity of three clinical p38alpha inhibitors==
		+	<StructureSection load='3zs5' size='340' side='right' caption='[[3zs5]], [[Resolution\|resolution]] 1.60Å' scene=''>
		+	== Structural highlights ==
		+	<table><tr><td colspan='2'>[[3zs5]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3ZS5 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3ZS5 FirstGlance]. <br>
		+	</td></tr><tr><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=BOG:B-OCTYLGLUCOSIDE'>BOG</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=SB2:4-[5-(4-FLUORO-PHENYL)-2-(4-METHANESULFINYL-PHENYL)-3H-IMIDAZOL-4-YL]-PYRIDINE'>SB2</scene><br>
		+	<tr><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat">[[1a9u\|1a9u]], [[1bl6\|1bl6]], [[1bl7\|1bl7]], [[1bmk\|1bmk]], [[1di9\|1di9]], [[1ian\|1ian]], [[1kv1\|1kv1]], [[1kv2\|1kv2]], [[1m7q\|1m7q]], [[1ouk\|1ouk]], [[1ouy\|1ouy]], [[1ove\|1ove]], [[1oz1\|1oz1]], [[1r39\|1r39]], [[1r3c\|1r3c]], [[1w7h\|1w7h]], [[1w82\|1w82]], [[1w83\|1w83]], [[1w84\|1w84]], [[1wbn\|1wbn]], [[1wbo\|1wbo]], [[1wbs\|1wbs]], [[1wbt\|1wbt]], [[1wbv\|1wbv]], [[1wbw\|1wbw]], [[1wfc\|1wfc]], [[1yqj\|1yqj]], [[1zyj\|1zyj]], [[1zz2\|1zz2]], [[1zzl\|1zzl]], [[2baj\|2baj]], [[2bak\|2bak]], [[2bal\|2bal]], [[2baq\|2baq]], [[2i0h\|2i0h]], [[2y8o\|2y8o]], [[2yis\|2yis]], [[2yiw\|2yiw]], [[2yix\|2yix]], [[3zsg\|3zsg]], [[3zsh\|3zsh]], [[3zsi\|3zsi]], [[3zya\|3zya]], [[4a9y\|4a9y]], [[4aa0\|4aa0]], [[4aa4\|4aa4]], [[4aa5\|4aa5]], [[4aac\|4aac]]</td></tr>
		+	<tr><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Mitogen-activated_protein_kinase Mitogen-activated protein kinase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.11.24 2.7.11.24] </span></td></tr>
		+	<tr><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3zs5 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3zs5 OCA], [http://www.rcsb.org/pdb/explore.do?structureId=3zs5 RCSB], [http://www.ebi.ac.uk/pdbsum/3zs5 PDBsum]</span></td></tr>
		+	<table>
		+	<div style="background-color:#fffaf0;">
		+	== Publication Abstract from PubMed ==
		+	The p38alpha mitogen-activated protein kinase regulates the synthesis of pro-inflammatory cytokines in response to stimulation by a diverse set of stress signals. Various different chemotypes and clinical candidates that inhibit p38alpha function have been reported over the years. In this publication, the novel structure of p38alpha cocrystallized with the clinical candidate TAK-715 is reported. Owing to the impact of crystallization conditions on the conformation of protein kinases (and in particular p38alpha), the structures of complexes of p38alpha with SB-203580, SCIO-469 and VX-745 have also been determined to enable in-depth comparison of ligand-induced protein conformations. The impact of experimental conditions on p38alpha-inhibitor complex structures, most importantly soaking versus cocrystallization, is discussed. Analysis of the structures and quantification of the protein-ligand interactions couples ligand-induced protein conformations to the number of interactions and to inhibitor selectivity against the human kinome. This shows that for the design of novel kinase inhibitors, selectivity is best obtained through maximization of the number of interactions throughout the ATP pocket and the exploitation of specific features in the active site.

-	~~{{STRUCTURE_3zs5\| PDB=3zs5 \| SCENE= }}~~	+	X-ray structure of p38alpha bound to TAK-715: comparison with three classic inhibitors.,Azevedo R, van Zeeland M, Raaijmakers H, Kazemier B, de Vlieg J, Oubrie A Acta Crystallogr D Biol Crystallogr. 2012 Aug;68(Pt 8):1041-50. Epub 2012 Jul 17. PMID:22868770<ref>PMID:22868770</ref>

-	~~===Structural basis for kinase selectivity~~ of ~~three clinical p38alpha inhibitors===~~	+	From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
		+	</div>

-	~~{{ABSTRACT_PUBMED_22868770}}~~	+	==See Also==
-		+	*[[Mitogen-activated protein kinase\|Mitogen-activated protein kinase]]
-	==~~About this Structure~~==	+	== References ==
-	[[~~3zs5~~]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3ZS5 OCA].	+	<references/>
-		+	__TOC__
-	==~~Reference~~==	+	</StructureSection>
-	<~~ref group="xtra">PMID:022868770<~~/~~ref~~><~~references group="xtra"~~/>	+
	[[Category: Homo sapiens]]		[[Category: Homo sapiens]]
	[[Category: Mitogen-activated protein kinase]]		[[Category: Mitogen-activated protein kinase]]

OCA at 04:58, 15 August 2012

OCA — Wed, 15 Aug 2012 04:58:28 GMT

←Older revision		Revision as of 04:58, 15 August 2012
Line 5:		Line 5:
	===Structural basis for kinase selectivity of three clinical p38alpha inhibitors===		===Structural basis for kinase selectivity of three clinical p38alpha inhibitors===

		+	{{ABSTRACT_PUBMED_22868770}}

	==About this Structure==		==About this Structure==
	[[3zs5]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3ZS5 OCA].		[[3zs5]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3ZS5 OCA].
		+
		+	==Reference==
		+	<ref group="xtra">PMID:022868770</ref><references group="xtra"/>
	[[Category: Homo sapiens]]		[[Category: Homo sapiens]]
	[[Category: Mitogen-activated protein kinase]]		[[Category: Mitogen-activated protein kinase]]

OCA at 06:13, 25 July 2012

OCA — Wed, 25 Jul 2012 06:13:00 GMT

←Older revision		Revision as of 06:13, 25 July 2012
Line 1:		Line 1:
-	[[Image:3zs5.~~jpg~~\|left\|200px]]	+	[[Image:3zs5.png\|left\|200px]]

	{{STRUCTURE_3zs5\| PDB=3zs5 \| SCENE= }}		{{STRUCTURE_3zs5\| PDB=3zs5 \| SCENE= }}

OCA at 07:45, 4 July 2012

OCA — Wed, 04 Jul 2012 07:45:40 GMT

←Older revision		Revision as of 07:45, 4 July 2012
Line 1:		Line 1:
-	~~'''Unreleased structure'''~~	+	[[Image:3zs5.jpg\|left\|200px]]

-	~~The entry~~ 3zs5 ~~is ON HOLD~~ ~~until Paper Publication~~	+	{{STRUCTURE_3zs5\| PDB=3zs5 \| SCENE= }}

-	~~Authors: Azevedo, R., van Zeeland, M., Raaijmakers, H.c.a., Kazemier, B., Oubrie, A.~~	+	===Structural basis for kinase selectivity of three clinical p38alpha inhibitors===

-	~~Description~~: ~~Structural basis for~~ kinase ~~selectivity of three clinical p38alpha inhibitors~~	+
		+	==About this Structure==
		+	[[3zs5]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3ZS5 OCA].
		+	[[Category: Homo sapiens]]
		+	[[Category: Mitogen-activated protein kinase]]
		+	[[Category: Azevedo, R.]]
		+	[[Category: Kazemier, B.]]
		+	[[Category: Oubrie, A.]]
		+	[[Category: Raaijmakers, H C.A.]]
		+	[[Category: Zeeland, M Van.]]
		+	[[Category: Sb-203580]]
		+	[[Category: Scio-469]]
		+	[[Category: Tak-715]]
		+	[[Category: Transferase]]
		+	[[Category: Vx-745]]