5r9j - Revision history

OCA at 11:38, 21 February 2024

OCA — Wed, 21 Feb 2024 11:38:24 GMT

←Older revision		Revision as of 11:38, 21 February 2024
Line 3:		Line 3:
	<StructureSection load='5r9j' size='340' side='right'caption='[[5r9j]], [[Resolution\|resolution]] 1.52Å' scene=''>		<StructureSection load='5r9j' size='340' side='right'caption='[[5r9j]], [[Resolution\|resolution]] 1.52Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
-	<table><tr><td colspan='2'>[[5r9j]] is a 1 chain structure with sequence from [~~http~~://en.wikipedia.org/wiki/~~Lk3_transgenic_mice Lk3 transgenic mice~~]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5R9J OCA]. For a <b>guided tour on the structure components</b> use [~~http~~://proteopedia.org/fgij/fg.htm?mol=5R9J FirstGlance]. <br>	+	<table><tr><td colspan='2'>[[5r9j]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Mus_musculus Mus musculus]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5R9J OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5R9J FirstGlance]. <br>
-	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=DMS:DIMETHYL+SULFOXIDE'>DMS</scene>, <scene name='pdbligand=LXS:3-ethyl-1-[(1~{R},8~{S},9~{S},10~{S})-10-oxidanyl-11-oxatricyclo[6.2.1.0^{2,7}]undeca-2(7),3,5-trien-9-yl]imidazolidine-2,4-dione'>LXS</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</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]] 1.52Å</td></tr>
-	<tr id='gene'><td class="sblockLbl"><b>[[Gene\|Gene:]]</b></td><td class="sblockDat">Mapk14, Crk1, Csbp1, Csbp2 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=10090 LK3 transgenic mice])</td></tr>	+	<tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=DMS:DIMETHYL+SULFOXIDE'>DMS</scene>, <scene name='pdbligand=LXS:3-ethyl-1-[(1~{R},8~{S},9~{S},10~{S})-10-oxidanyl-11-oxatricyclo[6.2.1.0^{2,7}]undeca-2(7),3,5-trien-9-yl]imidazolidine-2,4-dione'>LXS</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></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'>[https://proteopedia.org/fgij/fg.htm?mol=5r9j FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5r9j OCA], [https://pdbe.org/5r9j PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5r9j RCSB], [https://www.ebi.ac.uk/pdbsum/5r9j PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5r9j ProSAT]</span></td></tr>
-	<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[~~http~~://proteopedia.org/fgij/fg.htm?mol=5r9j FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5r9j OCA], [~~http~~://pdbe.org/5r9j PDBe], [~~http~~://www.rcsb.org/pdb/explore.do?structureId=5r9j RCSB], [~~http~~://www.ebi.ac.uk/pdbsum/5r9j PDBsum], [~~http~~://prosat.h-its.org/prosat/prosatexe?pdbcode=5r9j ProSAT]</span></td></tr>	+
	</table>		</table>
	== Function ==		== Function ==
-	[~~[http~~://www.uniprot.org/uniprot/MK14_MOUSE MK14_MOUSE]] 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. Phosphorylates S100A9 at 'Thr-113' (By similarity).<ref>PMID:10704466</ref> <ref>PMID:10943842</ref> <ref>PMID:11909979</ref> <ref>PMID:15735649</ref>	+	[https://www.uniprot.org/uniprot/MK14_MOUSE MK14_MOUSE] 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. Phosphorylates S100A9 at 'Thr-113' (By similarity).<ref>PMID:10704466</ref> <ref>PMID:10943842</ref> <ref>PMID:11909979</ref> <ref>PMID:15735649</ref>
-	~~<div style="background-color:#fffaf0;">~~	+
-	~~== Publication Abstract from PubMed ==~~	+
-	Nowadays, it is possible to combine X-ray crystallography and fragment screening in a medium throughput fashion to chemically probe the surfaces used by proteins to interact and use the outcome of the screens to systematically design protein-protein inhibitors. To prove it, we first performed a bioinformatics analysis of the Protein Data Bank protein complexes, which revealed over 400 cases where the crystal lattice of the target in the free form is such that large portions of the interacting surfaces are free from lattice contacts and therefore accessible to fragments during soaks. Among the tractable complexes identified, we then performed single fragment crystal screens on two particular interesting cases: the Il1beta-ILR and p38alpha-TAB1 complexes. The result of the screens showed that fragments tend to bind in clusters, highlighting the small-molecule hotspots on the surface of the target protein. In most of the cases, the hotspots overlapped with the binding sites of the interacting proteins.	+
-		+
-	Mining the PDB for Tractable Cases Where X-ray Crystallography Combined with Fragment Screens Can Be Used to Systematically Design Protein-Protein Inhibitors: Two Test Cases Illustrated by IL1beta-IL1R and p38alpha-TAB1 Complexes.,Nichols C, Ng J, Keshu A, Kelly G, Conte MR, Marber MS, Fraternali F, De Nicola GF J Med Chem. 2020 Jul 1. doi: 10.1021/acs.jmedchem.0c00403. PMID:32543856<ref>PMID:32543856</ref>	+
-		+
-	~~From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>~~	+
-	~~</div>~~	+
-	~~<div class="pdbe-citations 5r9j" style="background-color:#fffaf0;"></div~~>	+
	== References ==		== References ==
	<references/>		<references/>
Line 25:		Line 15:
	</StructureSection>		</StructureSection>
	[[Category: Large Structures]]		[[Category: Large Structures]]
-	[[Category: ~~Lk3 transgenic mice~~]]	+	[[Category: Mus musculus]]
-	[[Category: ~~Mitogen-activated protein kinase~~]]	+	[[Category: De Nicola GF]]
-	[[Category: Nichols~~, C E]]~~	+	[[Category: Nichols CE]]
-	~~[[Category: Nicola, G F.De]]~~	+
-	~~[[Category: Kinase]]~~	+
-	~~[[Category: Mapk14]]~~	+
-	~~[[Category: P38]]~~	+
-	~~[[Category: Pandda]]~~	+
-	~~[[Category: Sgc - diamond i04-1 fragment screening]]~~	+
-	~~[[Category: Transferase]]~~	+
-	~~[[Category: Xchemexplorer~~]]	+

OCA at 05:42, 5 August 2020

OCA — Wed, 05 Aug 2020 05:42:00 GMT

←Older revision		Revision as of 05:42, 5 August 2020
Line 1:		Line 1:

	==PanDDA analysis group deposition Form1 MAP kinase p38-alpha -- Fragment N14231a in complex with MAP kinase p38-alpha==		==PanDDA analysis group deposition Form1 MAP kinase p38-alpha -- Fragment N14231a in complex with MAP kinase p38-alpha==
-	<StructureSection load='5r9j' size='340' side='right'caption='[[5r9j]]' scene=''>	+	<StructureSection load='5r9j' size='340' side='right'caption='[[5r9j]], [[Resolution\|resolution]] 1.52Å' 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=5R9J OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=5R9J FirstGlance]. <br>	+	<table><tr><td colspan='2'>[[5r9j]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Lk3_transgenic_mice Lk3 transgenic mice]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5R9J OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=5R9J FirstGlance]. <br>
-	</td></tr><tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://proteopedia.org/fgij/fg.htm?mol=5r9j FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5r9j OCA], [http://pdbe.org/5r9j PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5r9j RCSB], [http://www.ebi.ac.uk/pdbsum/5r9j PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5r9j 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=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=DMS:DIMETHYL+SULFOXIDE'>DMS</scene>, <scene name='pdbligand=LXS:3-ethyl-1-[(1~{R},8~{S},9~{S},10~{S})-10-oxidanyl-11-oxatricyclo[6.2.1.0^{2,7}]undeca-2(7),3,5-trien-9-yl]imidazolidine-2,4-dione'>LXS</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></td></tr>
		+	<tr id='gene'><td class="sblockLbl"><b>[[Gene\|Gene:]]</b></td><td class="sblockDat">Mapk14, Crk1, Csbp1, Csbp2 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=10090 LK3 transgenic mice])</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://proteopedia.org/fgij/fg.htm?mol=5r9j FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5r9j OCA], [http://pdbe.org/5r9j PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5r9j RCSB], [http://www.ebi.ac.uk/pdbsum/5r9j PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5r9j ProSAT]</span></td></tr>
	</table>		</table>
		+	== Function ==
		+	[[http://www.uniprot.org/uniprot/MK14_MOUSE MK14_MOUSE]] 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. Phosphorylates S100A9 at 'Thr-113' (By similarity).<ref>PMID:10704466</ref> <ref>PMID:10943842</ref> <ref>PMID:11909979</ref> <ref>PMID:15735649</ref>
		+	<div style="background-color:#fffaf0;">
		+	== Publication Abstract from PubMed ==
		+	Nowadays, it is possible to combine X-ray crystallography and fragment screening in a medium throughput fashion to chemically probe the surfaces used by proteins to interact and use the outcome of the screens to systematically design protein-protein inhibitors. To prove it, we first performed a bioinformatics analysis of the Protein Data Bank protein complexes, which revealed over 400 cases where the crystal lattice of the target in the free form is such that large portions of the interacting surfaces are free from lattice contacts and therefore accessible to fragments during soaks. Among the tractable complexes identified, we then performed single fragment crystal screens on two particular interesting cases: the Il1beta-ILR and p38alpha-TAB1 complexes. The result of the screens showed that fragments tend to bind in clusters, highlighting the small-molecule hotspots on the surface of the target protein. In most of the cases, the hotspots overlapped with the binding sites of the interacting proteins.
		+
		+	Mining the PDB for Tractable Cases Where X-ray Crystallography Combined with Fragment Screens Can Be Used to Systematically Design Protein-Protein Inhibitors: Two Test Cases Illustrated by IL1beta-IL1R and p38alpha-TAB1 Complexes.,Nichols C, Ng J, Keshu A, Kelly G, Conte MR, Marber MS, Fraternali F, De Nicola GF J Med Chem. 2020 Jul 1. doi: 10.1021/acs.jmedchem.0c00403. PMID:32543856<ref>PMID:32543856</ref>
		+
		+	From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
		+	</div>
		+	<div class="pdbe-citations 5r9j" style="background-color:#fffaf0;"></div>
		+	== References ==
		+	<references/>
	__TOC__		__TOC__
	</StructureSection>		</StructureSection>
	[[Category: Large Structures]]		[[Category: Large Structures]]
-	[[Category: ~~De Nicola GF~~]]	+	[[Category: Lk3 transgenic mice]]
-	[[Category: Nichols CE]]	+	[[Category: Mitogen-activated protein kinase]]
		+	[[Category: Nichols, C E]]
		+	[[Category: Nicola, G F.De]]
		+	[[Category: Kinase]]
		+	[[Category: Mapk14]]
		+	[[Category: P38]]
		+	[[Category: Pandda]]
		+	[[Category: Sgc - diamond i04-1 fragment screening]]
		+	[[Category: Transferase]]
		+	[[Category: Xchemexplorer]]

OCA at 10:43, 22 July 2020

OCA — Wed, 22 Jul 2020 10:43:12 GMT

←Older revision		Revision as of 10:43, 22 July 2020
Line 1:		Line 1:
-	'''Unreleased structure'''

-	~~The entry 5r9j is ON HOLD~~	+	==PanDDA analysis group deposition Form1 MAP kinase p38-alpha -- Fragment N14231a in complex with MAP kinase p38-alpha==
-		+	<StructureSection load='5r9j' size='340' side='right'caption='[[5r9j]]' scene=''>
-	~~Authors: De Nicola, G.F., Nichols, C.E.~~	+	== Structural highlights ==
-		+	<table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5R9J OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=5R9J FirstGlance]. <br>
-	~~Description:~~ PanDDA analysis group deposition Form1 MAP kinase p38-alpha --Fragment N14231a in complex with MAP kinase p38-alpha	+	</td></tr><tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://proteopedia.org/fgij/fg.htm?mol=5r9j FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5r9j OCA], [http://pdbe.org/5r9j PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5r9j RCSB], [http://www.ebi.ac.uk/pdbsum/5r9j PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5r9j ProSAT]</span></td></tr>
-	[[Category: ~~Unreleased~~ Structures]]	+	</table>
-	[[Category: De Nicola~~, G.F~~]]	+	__TOC__
-	[[Category: Nichols~~, C.E~~]]	+	</StructureSection>
		+	[[Category: Large Structures]]
		+	[[Category: De Nicola GF]]
		+	[[Category: Nichols CE]]

OCA at 08:08, 18 March 2020

OCA — Wed, 18 Mar 2020 08:08:31 GMT

←Older revision		Revision as of 08:08, 18 March 2020
Line 3:		Line 3:
	The entry 5r9j is ON HOLD		The entry 5r9j is ON HOLD

-	Authors: ~~De_Nicola~~, G.F., Nichols, C.E.	+	Authors: De Nicola, G.F., Nichols, C.E.

	Description: PanDDA analysis group deposition Form1 MAP kinase p38-alpha --Fragment N14231a in complex with MAP kinase p38-alpha		Description: PanDDA analysis group deposition Form1 MAP kinase p38-alpha --Fragment N14231a in complex with MAP kinase p38-alpha
	[[Category: Unreleased Structures]]		[[Category: Unreleased Structures]]
-	[[Category: ~~De_nicola~~, G.F]]	+	[[Category: De Nicola, G.F]]
	[[Category: Nichols, C.E]]		[[Category: Nichols, C.E]]

OCA: Protected "5r9j" [edit=sysop:move=sysop]

OCA — Wed, 11 Mar 2020 05:51:20 GMT

Protected "5r9j" [edit=sysop:move=sysop]

←Older revision

Revision as of 05:51, 11 March 2020

OCA: New page: '''Unreleased structure''' The entry 5r9j is ON HOLD Authors: De_Nicola, G.F., Nichols, C.E. Description: PanDDA analysis group deposition Form1 MAP kinase p38-alpha --Fragment N14231a...

OCA — Wed, 11 Mar 2020 05:51:19 GMT

New page: '''Unreleased structure''' The entry 5r9j is ON HOLD Authors: De_Nicola, G.F., Nichols, C.E. Description: PanDDA analysis group deposition Form1 MAP kinase p38-alpha --Fragment N14231a...

New page

'''Unreleased structure'''

The entry 5r9j is ON HOLD

Authors: De_Nicola, G.F., Nichols, C.E.

Description: PanDDA analysis group deposition Form1 MAP kinase p38-alpha --Fragment N14231a in complex with MAP kinase p38-alpha
[[Category: Unreleased Structures]]
[[Category: De_nicola, G.F]]
[[Category: Nichols, C.E]]