3jxw - Revision history

OCA at 10:14, 21 February 2024

2024-02-21T10:14:01Z

←Older revision		Revision as of 10:14, 21 February 2024
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	==Discovery of 3H-benzo[4,5]thieno[3,2-d]pyrimidin-4-ones as Potent, Highly Selective and Orally Bioavailable Pim Kinases Inhibitors==		==Discovery of 3H-benzo[4,5]thieno[3,2-d]pyrimidin-4-ones as Potent, Highly Selective and Orally Bioavailable Pim Kinases Inhibitors==
-	<StructureSection load='3jxw' size='340' side='right' caption='[[3jxw]], [[Resolution\|resolution]] 2.80Å' scene=''>	+	<StructureSection load='3jxw' size='340' side='right'caption='[[3jxw]], [[Resolution\|resolution]] 2.80Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
-	<table><tr><td colspan='2'>[[3jxw]] 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=3JXW OCA]. For a <b>guided tour on the structure components</b> use [~~http~~://~~oca~~.~~weizmann.ac.il/oca-docs~~/fgij/fg.htm?mol=3JXW FirstGlance]. <br>	+	<table><tr><td colspan='2'>[[3jxw]] 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=3JXW OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3JXW FirstGlance]. <br>
-	</td></tr><tr id='~~ligand~~'><td class="sblockLbl"><b>[[~~Ligand~~\|~~Ligands~~:]]</b></td><td class="sblockDat">~~<scene name='pdbligand=LXG:8~~-[~~(E)-2-CYCLOPROPYLETHENYL]-2-~~[~~(DIMETHYLAMINO)METHYL~~][1]~~BENZOTHIENO[3,~~2~~-D]PYRIMIDIN-4(3H)-ONE'>LXG</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]] 2.8Å</td></tr>
-	<tr id='~~gene~~'><td class="sblockLbl"><b>[[~~Gene~~\|~~Gene~~:]]</b></td><td class="sblockDat"~~>PIM1 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&~~id~~=9606 HUMAN])</td></tr>~~	+	<tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=LXG:8-[(E)-2-CYCLOPROPYLETHENYL]-2-[(DIMETHYLAMINO)METHYL][1]BENZOTHIENO[3,2-D]PYRIMIDIN-4(3H)-ONE'>LXG</scene></td></tr>
-	~~<tr id='activity'><td class~~="~~sblockLbl~~"><~~b>Activity:</b></td><td class~~=~~"sblockDat"><span class~~=~~'plainlinks'>[http~~:~~//en.wikipedia.org/wiki/Non~~-~~specific_serine/threonine_protein_kinase Non~~-~~specific serine/threonine protein kinase~~]~~, with EC number [http://www.brenda~~-~~enzymes.info/php/result_flat.php4?ecno=~~2~~.7.11.~~1 2~~.7.11.1~~] </~~span~~></td></tr>	+	<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=3jxw FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3jxw OCA], [https://pdbe.org/3jxw PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3jxw RCSB], [https://www.ebi.ac.uk/pdbsum/3jxw PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3jxw 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=3jxw FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3jxw OCA], [~~http~~://pdbe.org/3jxw PDBe], [~~http~~://www.rcsb.org/pdb/explore.do?structureId=3jxw RCSB], [~~http~~://www.ebi.ac.uk/pdbsum/3jxw PDBsum], [~~http~~://prosat.h-its.org/prosat/prosatexe?pdbcode=3jxw ProSAT]</span></td></tr>	+
	</table>		</table>
	== Function ==		== Function ==
-	[~~[http~~://www.uniprot.org/uniprot/PIM1_HUMAN PIM1_HUMAN]] Proto-oncogene with serine/threonine kinase activity involved in cell survival and cell proliferation and thus providing a selective advantage in tumorigenesis. Exerts its oncogenic activity through: the regulation of MYC transcriptional activity, the regulation of cell cycle progression and by phosphorylation and inhibition of proapoptotic proteins (BAD, MAP3K5, FOXO3). Phosphorylation of MYC leads to an increase of MYC protein stability and thereby an increase of transcriptional activity. The stabilization of MYC exerted by PIM1 might explain partly the strong synergism between these two oncogenes in tumorigenesis. Mediates survival signaling through phosphorylation of BAD, which induces release of the anti-apoptotic protein Bcl-X(L)/BCL2L1. Phosphorylation of MAP3K5, an other proapoptotic protein, by PIM1, significantly decreases MAP3K5 kinase activity and inhibits MAP3K5-mediated phosphorylation of JNK and JNK/p38MAPK subsequently reducing caspase-3 activation and cell apoptosis. Stimulates cell cycle progression at the G1-S and G2-M transitions by phosphorylation of CDC25A and CDC25C. Phosphorylation of CDKN1A, a regulator of cell cycle progression at G1, results in the relocation of CDKN1A to the cytoplasm and enhanced CDKN1A protein stability. Promote cell cycle progression and tumorigenesis by down-regulating expression of a regulator of cell cycle progression, CDKN1B, at both transcriptional and post-translational levels. Phosphorylation of CDKN1B,induces 14-3-3-proteins binding, nuclear export and proteasome-dependent degradation. May affect the structure or silencing of chromatin by phosphorylating HP1 gamma/CBX3. Acts also as a regulator of homing and migration of bone marrow cells involving functional interaction with the CXCL12-CXCR4 signaling axis.<ref>PMID:1825810</ref> <ref>PMID:10664448</ref> <ref>PMID:12431783</ref> <ref>PMID:15528381</ref> <ref>PMID:16356754</ref> <ref>PMID:18593906</ref> <ref>PMID:19749799</ref>	+	[https://www.uniprot.org/uniprot/PIM1_HUMAN PIM1_HUMAN] Proto-oncogene with serine/threonine kinase activity involved in cell survival and cell proliferation and thus providing a selective advantage in tumorigenesis. Exerts its oncogenic activity through: the regulation of MYC transcriptional activity, the regulation of cell cycle progression and by phosphorylation and inhibition of proapoptotic proteins (BAD, MAP3K5, FOXO3). Phosphorylation of MYC leads to an increase of MYC protein stability and thereby an increase of transcriptional activity. The stabilization of MYC exerted by PIM1 might explain partly the strong synergism between these two oncogenes in tumorigenesis. Mediates survival signaling through phosphorylation of BAD, which induces release of the anti-apoptotic protein Bcl-X(L)/BCL2L1. Phosphorylation of MAP3K5, an other proapoptotic protein, by PIM1, significantly decreases MAP3K5 kinase activity and inhibits MAP3K5-mediated phosphorylation of JNK and JNK/p38MAPK subsequently reducing caspase-3 activation and cell apoptosis. Stimulates cell cycle progression at the G1-S and G2-M transitions by phosphorylation of CDC25A and CDC25C. Phosphorylation of CDKN1A, a regulator of cell cycle progression at G1, results in the relocation of CDKN1A to the cytoplasm and enhanced CDKN1A protein stability. Promote cell cycle progression and tumorigenesis by down-regulating expression of a regulator of cell cycle progression, CDKN1B, at both transcriptional and post-translational levels. Phosphorylation of CDKN1B,induces 14-3-3-proteins binding, nuclear export and proteasome-dependent degradation. May affect the structure or silencing of chromatin by phosphorylating HP1 gamma/CBX3. Acts also as a regulator of homing and migration of bone marrow cells involving functional interaction with the CXCL12-CXCR4 signaling axis.<ref>PMID:1825810</ref> <ref>PMID:10664448</ref> <ref>PMID:12431783</ref> <ref>PMID:15528381</ref> <ref>PMID:16356754</ref> <ref>PMID:18593906</ref> <ref>PMID:19749799</ref>
	== Evolutionary Conservation ==		== Evolutionary Conservation ==
	[[Image:Consurf_key_small.gif\|200px\|right]]		[[Image:Consurf_key_small.gif\|200px\|right]]
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	==See Also==		==See Also==
-	*[[~~Proto-oncogene serine~~/threonine-protein kinase\|~~Proto-oncogene serine~~/threonine-protein kinase]]	+	*[[Serine/threonine protein kinase 3D structures\|Serine/threonine protein kinase 3D structures]]
-	*[[~~Student Project 6 for UMass Chemistry 423 Spring 2015~~\|~~Student Project 6 for UMass Chemistry 423 Spring 2015~~]]	+	*[[3D structures of pim-1\|3D structures of pim-1]]
	== References ==		== References ==
	<references/>		<references/>
	__TOC__		__TOC__
	</StructureSection>		</StructureSection>
-	[[Category: ~~Human~~]]	+	[[Category: Homo sapiens]]
-	[[Category: ~~Non-specific serine/threonine protein kinase~~]]	+	[[Category: Large Structures]]
-	[[Category: Stoll~~, V S]]~~	+	[[Category: Stoll VS]]
-	~~[[Category: Alternative initiation]]~~	+
-	~~[[Category: Atp-binding]]~~	+
-	~~[[Category: Cell membrane]]~~	+
-	~~[[Category: Cytoplasm]]~~	+
-	~~[[Category: Kinase]]~~	+
-	~~[[Category: Manganese]]~~	+
-	~~[[Category: Membrane]]~~	+
-	~~[[Category: Metal-binding]]~~	+
-	~~[[Category: Nucleotide-binding]]~~	+
-	~~[[Category: Nucleus]]~~	+
-	~~[[Category: Phosphoprotein]]~~	+
-	~~[[Category: Pim-1]]~~	+
-	~~[[Category: Polymorphism]]~~	+
-	~~[[Category: Proto-oncogene]]~~	+
-	~~[[Category: Serine/threonine-protein kinase]]~~	+
-	~~[[Category: Transferase~~]]	+

OCA at 09:32, 26 December 2018

2018-12-26T09:32:19Z

←Older revision		Revision as of 09:32, 26 December 2018
Line 1:		Line 1:
		+
	==Discovery of 3H-benzo[4,5]thieno[3,2-d]pyrimidin-4-ones as Potent, Highly Selective and Orally Bioavailable Pim Kinases Inhibitors==		==Discovery of 3H-benzo[4,5]thieno[3,2-d]pyrimidin-4-ones as Potent, Highly Selective and Orally Bioavailable Pim Kinases Inhibitors==
	<StructureSection load='3jxw' size='340' side='right' caption='[[3jxw]], [[Resolution\|resolution]] 2.80Å' scene=''>		<StructureSection load='3jxw' size='340' side='right' caption='[[3jxw]], [[Resolution\|resolution]] 2.80Å' scene=''>
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	<tr id='gene'><td class="sblockLbl"><b>[[Gene\|Gene:]]</b></td><td class="sblockDat">PIM1 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr>		<tr id='gene'><td class="sblockLbl"><b>[[Gene\|Gene:]]</b></td><td class="sblockDat">PIM1 ([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/Non-specific_serine/threonine_protein_kinase Non-specific serine/threonine protein kinase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.11.1 2.7.11.1] </span></td></tr>		<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Non-specific_serine/threonine_protein_kinase Non-specific serine/threonine protein kinase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.11.1 2.7.11.1] </span></td></tr>
-	<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3jxw FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3jxw OCA], [http://pdbe.org/3jxw PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=3jxw RCSB], [http://www.ebi.ac.uk/pdbsum/3jxw 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=3jxw FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3jxw OCA], [http://pdbe.org/3jxw PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=3jxw RCSB], [http://www.ebi.ac.uk/pdbsum/3jxw PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=3jxw ProSAT]</span></td></tr>
	</table>		</table>
	== Function ==		== Function ==
Line 14:		Line 15:
	Check<jmol>		Check<jmol>
	<jmolCheckbox>		<jmolCheckbox>
-	<scriptWhenChecked>select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/jx/3jxw_consurf.spt"</scriptWhenChecked>	+	<scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/jx/3jxw_consurf.spt"</scriptWhenChecked>
	<scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked>		<scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked>
	<text>to colour the structure by Evolutionary Conservation</text>		<text>to colour the structure by Evolutionary Conservation</text>
Line 34:		Line 35:
	[[Category: Atp-binding]]		[[Category: Atp-binding]]
	[[Category: Cell membrane]]		[[Category: Cell membrane]]
		+	[[Category: Cytoplasm]]
	[[Category: Kinase]]		[[Category: Kinase]]
	[[Category: Manganese]]		[[Category: Manganese]]
Line 42:		Line 44:
	[[Category: Phosphoprotein]]		[[Category: Phosphoprotein]]
	[[Category: Pim-1]]		[[Category: Pim-1]]
		+	[[Category: Polymorphism]]
	[[Category: Proto-oncogene]]		[[Category: Proto-oncogene]]
	[[Category: Serine/threonine-protein kinase]]		[[Category: Serine/threonine-protein kinase]]
	[[Category: Transferase]]		[[Category: Transferase]]

OCA at 19:12, 9 February 2016

2016-02-09T19:12:39Z

←Older revision		Revision as of 19:12, 9 February 2016
Line 2:		Line 2:
	<StructureSection load='3jxw' size='340' side='right' caption='[[3jxw]], [[Resolution\|resolution]] 2.80Å' scene=''>		<StructureSection load='3jxw' size='340' side='right' caption='[[3jxw]], [[Resolution\|resolution]] 2.80Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
-	<table><tr><td colspan='2'>[[3jxw]] 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=3JXW OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3JXW FirstGlance]. <br>	+	<table><tr><td colspan='2'>[[3jxw]] 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=3JXW OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3JXW FirstGlance]. <br>
	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=LXG:8-[(E)-2-CYCLOPROPYLETHENYL]-2-[(DIMETHYLAMINO)METHYL][1]BENZOTHIENO[3,2-D]PYRIMIDIN-4(3H)-ONE'>LXG</scene></td></tr>		</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=LXG:8-[(E)-2-CYCLOPROPYLETHENYL]-2-[(DIMETHYLAMINO)METHYL][1]BENZOTHIENO[3,2-D]PYRIMIDIN-4(3H)-ONE'>LXG</scene></td></tr>
-	<tr id='gene'><td class="sblockLbl"><b>[[Gene\|Gene:]]</b></td><td class="sblockDat">PIM1 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 ~~Homo sapiens~~])</td></tr>	+	<tr id='gene'><td class="sblockLbl"><b>[[Gene\|Gene:]]</b></td><td class="sblockDat">PIM1 ([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/Non-specific_serine/threonine_protein_kinase Non-specific serine/threonine protein kinase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.11.1 2.7.11.1] </span></td></tr>		<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Non-specific_serine/threonine_protein_kinase Non-specific serine/threonine protein kinase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.11.1 2.7.11.1] </span></td></tr>
-	<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3jxw FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3jxw OCA], [http://www.rcsb.org/pdb/explore.do?structureId=3jxw RCSB], [http://www.ebi.ac.uk/pdbsum/3jxw 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=3jxw FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3jxw OCA], [http://pdbe.org/3jxw PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=3jxw RCSB], [http://www.ebi.ac.uk/pdbsum/3jxw PDBsum]</span></td></tr>
	</table>		</table>
	== Function ==		== Function ==
Line 18:		Line 18:
	<text>to colour the structure by Evolutionary Conservation</text>		<text>to colour the structure by Evolutionary Conservation</text>
	</jmolCheckbox>		</jmolCheckbox>
-	</jmol>, as determined by [http://consurfdb.tau.ac.il/ ConSurfDB]. You may read the [[Conservation%2C_Evolutionary\|explanation]] of the method and the full data available from [http://bental.tau.ac.il/new_ConSurfDB/~~chain_selection~~.php?pdb_ID=~~2ata~~ ConSurf].	+	</jmol>, as determined by [http://consurfdb.tau.ac.il/ ConSurfDB]. You may read the [[Conservation%2C_Evolutionary\|explanation]] of the method and the full data available from [http://bental.tau.ac.il/new_ConSurfDB/main_output.php?pdb_ID=3jxw ConSurf].
	<div style="clear:both"></div>		<div style="clear:both"></div>

	==See Also==		==See Also==
	*[[Proto-oncogene serine/threonine-protein kinase\|Proto-oncogene serine/threonine-protein kinase]]		*[[Proto-oncogene serine/threonine-protein kinase\|Proto-oncogene serine/threonine-protein kinase]]
		+	*[[Student Project 6 for UMass Chemistry 423 Spring 2015\|Student Project 6 for UMass Chemistry 423 Spring 2015]]
	== References ==		== References ==
	<references/>		<references/>
	__TOC__		__TOC__
	</StructureSection>		</StructureSection>
-	[[Category: ~~Homo sapiens~~]]	+	[[Category: Human]]
	[[Category: Non-specific serine/threonine protein kinase]]		[[Category: Non-specific serine/threonine protein kinase]]
	[[Category: Stoll, V S]]		[[Category: Stoll, V S]]

OCA at 08:56, 25 December 2014

2014-12-25T08:56:27Z

←Older revision		Revision as of 08:56, 25 December 2014
Line 8:		Line 8:
	<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=3jxw FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3jxw OCA], [http://www.rcsb.org/pdb/explore.do?structureId=3jxw RCSB], [http://www.ebi.ac.uk/pdbsum/3jxw 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=3jxw FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3jxw OCA], [http://www.rcsb.org/pdb/explore.do?structureId=3jxw RCSB], [http://www.ebi.ac.uk/pdbsum/3jxw PDBsum]</span></td></tr>
	</table>		</table>
		+	== Function ==
		+	[[http://www.uniprot.org/uniprot/PIM1_HUMAN PIM1_HUMAN]] Proto-oncogene with serine/threonine kinase activity involved in cell survival and cell proliferation and thus providing a selective advantage in tumorigenesis. Exerts its oncogenic activity through: the regulation of MYC transcriptional activity, the regulation of cell cycle progression and by phosphorylation and inhibition of proapoptotic proteins (BAD, MAP3K5, FOXO3). Phosphorylation of MYC leads to an increase of MYC protein stability and thereby an increase of transcriptional activity. The stabilization of MYC exerted by PIM1 might explain partly the strong synergism between these two oncogenes in tumorigenesis. Mediates survival signaling through phosphorylation of BAD, which induces release of the anti-apoptotic protein Bcl-X(L)/BCL2L1. Phosphorylation of MAP3K5, an other proapoptotic protein, by PIM1, significantly decreases MAP3K5 kinase activity and inhibits MAP3K5-mediated phosphorylation of JNK and JNK/p38MAPK subsequently reducing caspase-3 activation and cell apoptosis. Stimulates cell cycle progression at the G1-S and G2-M transitions by phosphorylation of CDC25A and CDC25C. Phosphorylation of CDKN1A, a regulator of cell cycle progression at G1, results in the relocation of CDKN1A to the cytoplasm and enhanced CDKN1A protein stability. Promote cell cycle progression and tumorigenesis by down-regulating expression of a regulator of cell cycle progression, CDKN1B, at both transcriptional and post-translational levels. Phosphorylation of CDKN1B,induces 14-3-3-proteins binding, nuclear export and proteasome-dependent degradation. May affect the structure or silencing of chromatin by phosphorylating HP1 gamma/CBX3. Acts also as a regulator of homing and migration of bone marrow cells involving functional interaction with the CXCL12-CXCR4 signaling axis.<ref>PMID:1825810</ref> <ref>PMID:10664448</ref> <ref>PMID:12431783</ref> <ref>PMID:15528381</ref> <ref>PMID:16356754</ref> <ref>PMID:18593906</ref> <ref>PMID:19749799</ref>
	== Evolutionary Conservation ==		== Evolutionary Conservation ==
	[[Image:Consurf_key_small.gif\|200px\|right]]		[[Image:Consurf_key_small.gif\|200px\|right]]
Line 21:		Line 23:
	==See Also==		==See Also==
	*[[Proto-oncogene serine/threonine-protein kinase\|Proto-oncogene serine/threonine-protein kinase]]		*[[Proto-oncogene serine/threonine-protein kinase\|Proto-oncogene serine/threonine-protein kinase]]
		+	== References ==
		+	<references/>
	__TOC__		__TOC__
	</StructureSection>		</StructureSection>

OCA at 17:49, 18 December 2014

2014-12-18T17:49:47Z

←Older revision		Revision as of 17:49, 18 December 2014
Line 1:		Line 1:
-	~~{{STRUCTURE_3jxw\| PDB=3jxw \| SCENE= }}~~	+	==Discovery of 3H-benzo[4,5]thieno[3,2-d]pyrimidin-4-ones as Potent, Highly Selective and Orally Bioavailable Pim Kinases Inhibitors==
-	===Discovery of 3H-benzo[4,5]thieno[3,2-d]pyrimidin-4-ones as Potent, Highly Selective and Orally Bioavailable Pim Kinases Inhibitors===	+	<StructureSection load='3jxw' size='340' side='right' caption='[[3jxw]], [[Resolution\|resolution]] 2.80Å' scene=''>
		+	== Structural highlights ==
		+	<table><tr><td colspan='2'>[[3jxw]] 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=3JXW OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3JXW FirstGlance]. <br>
		+	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=LXG:8-[(E)-2-CYCLOPROPYLETHENYL]-2-[(DIMETHYLAMINO)METHYL][1]BENZOTHIENO[3,2-D]PYRIMIDIN-4(3H)-ONE'>LXG</scene></td></tr>
		+	<tr id='gene'><td class="sblockLbl"><b>[[Gene\|Gene:]]</b></td><td class="sblockDat">PIM1 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 Homo sapiens])</td></tr>
		+	<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Non-specific_serine/threonine_protein_kinase Non-specific serine/threonine protein kinase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.11.1 2.7.11.1] </span></td></tr>
		+	<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3jxw FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3jxw OCA], [http://www.rcsb.org/pdb/explore.do?structureId=3jxw RCSB], [http://www.ebi.ac.uk/pdbsum/3jxw PDBsum]</span></td></tr>
		+	</table>
		+	== Evolutionary Conservation ==
		+	[[Image:Consurf_key_small.gif\|200px\|right]]
		+	Check<jmol>
		+	<jmolCheckbox>
		+	<scriptWhenChecked>select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/jx/3jxw_consurf.spt"</scriptWhenChecked>
		+	<scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked>
		+	<text>to colour the structure by Evolutionary Conservation</text>
		+	</jmolCheckbox>
		+	</jmol>, as determined by [http://consurfdb.tau.ac.il/ ConSurfDB]. You may read the [[Conservation%2C_Evolutionary\|explanation]] of the method and the full data available from [http://bental.tau.ac.il/new_ConSurfDB/chain_selection.php?pdb_ID=2ata ConSurf].
		+	<div style="clear:both"></div>

-	==~~Function~~==	+	==See Also==
-	[[~~http://www.uniprot.org/uniprot/PIM1_HUMAN PIM1_HUMAN]]~~ Proto-oncogene ~~with~~ serine/threonine kinase activity involved in cell survival and cell proliferation and thus providing a selective advantage in tumorigenesis. Exerts its oncogenic activity through: the regulation of MYC transcriptional activity, the regulation of cell cycle progression and by phosphorylation and inhibition of proapoptotic proteins (BAD, MAP3K5, FOXO3). Phosphorylation of MYC leads to an increase of MYC protein stability and thereby an increase of transcriptional activity. The stabilization of MYC exerted by PIM1 might explain partly the strong synergism between these two oncogenes in tumorigenesis. Mediates survival signaling through phosphorylation of BAD, which induces release of the anti-~~apoptotic protein Bcl-X(L)/BCL2L1. Phosphorylation of MAP3K5, an other proapoptotic~~ protein~~, by PIM1, significantly decreases MAP3K5~~ kinase ~~activity and inhibits MAP3K5~~-~~mediated phosphorylation of JNK and JNK~~/~~p38MAPK subsequently reducing caspase-3 activation and cell apoptosis. Stimulates cell cycle progression at the G1-S and G2~~-~~M transitions by phosphorylation of CDC25A and CDC25C. Phosphorylation of CDKN1A, a regulator of cell cycle progression at G1, results in the relocation of CDKN1A to the cytoplasm and enhanced CDKN1A~~ protein stability. Promote cell cycle progression and tumorigenesis by down-regulating expression of a regulator of cell cycle progression, CDKN1B, at both transcriptional and post-translational levels. Phosphorylation of CDKN1B,induces 14-3-3-proteins binding, nuclear export and proteasome-dependent degradation. May affect the structure or silencing of chromatin by phosphorylating HP1 gamma/CBX3. Acts also as a regulator of homing and migration of bone marrow cells involving functional interaction with the CXCL12-CXCR4 signaling axis.<ref>PMID:1825810</ref><ref>PMID:10664448</ref><ref>PMID:12431783</ref><ref>PMID:15528381</ref><ref>PMID:16356754</ref><ref>PMID:18593906</ref><ref>PMID:19749799</ref>	+	*[[Proto-oncogene serine/threonine-protein kinase\|Proto-oncogene serine/threonine-protein kinase]]
-		+	__TOC__
-	~~==About this Structure==~~	+	</StructureSection>
-	~~[[3jxw~~]] 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=3JXW OCA].	+
-		+
-	~~==Reference==~~	+
-	~~<references group="xtra"/>~~<~~references~~/>	+
	[[Category: Homo sapiens]]		[[Category: Homo sapiens]]
	[[Category: Non-specific serine/threonine protein kinase]]		[[Category: Non-specific serine/threonine protein kinase]]
-	[[Category: Stoll, V S.]]	+	[[Category: Stoll, V S]]
	[[Category: Alternative initiation]]		[[Category: Alternative initiation]]
	[[Category: Atp-binding]]		[[Category: Atp-binding]]

OCA: Protected "3jxw" [edit=sysop:move=sysop]

2013-03-27T09:23:43Z

Protected "3jxw" [edit=sysop:move=sysop]

←Older revision

Revision as of 09:23, 27 March 2013

OCA at 09:23, 27 March 2013

2013-03-27T09:23:39Z

←Older revision		Revision as of 09:23, 27 March 2013
Line 1:		Line 1:
-	{{Seed}}
-	[[Image:3jxw.jpg\|left\|200px]]
-
-	<!--
-	The line below this paragraph, containing "STRUCTURE_3jxw", creates the "Structure Box" on the page.
-	You may change the PDB parameter (which sets the PDB file loaded into the applet)
-	or the SCENE parameter (which sets the initial scene displayed when the page is loaded),
-	or leave the SCENE parameter empty for the default display.
-	-->
	{{STRUCTURE_3jxw\| PDB=3jxw \| SCENE= }}		{{STRUCTURE_3jxw\| PDB=3jxw \| SCENE= }}
-
	===Discovery of 3H-benzo[4,5]thieno[3,2-d]pyrimidin-4-ones as Potent, Highly Selective and Orally Bioavailable Pim Kinases Inhibitors===		===Discovery of 3H-benzo[4,5]thieno[3,2-d]pyrimidin-4-ones as Potent, Highly Selective and Orally Bioavailable Pim Kinases Inhibitors===

		+	==Function==
		+	[[http://www.uniprot.org/uniprot/PIM1_HUMAN PIM1_HUMAN]] Proto-oncogene with serine/threonine kinase activity involved in cell survival and cell proliferation and thus providing a selective advantage in tumorigenesis. Exerts its oncogenic activity through: the regulation of MYC transcriptional activity, the regulation of cell cycle progression and by phosphorylation and inhibition of proapoptotic proteins (BAD, MAP3K5, FOXO3). Phosphorylation of MYC leads to an increase of MYC protein stability and thereby an increase of transcriptional activity. The stabilization of MYC exerted by PIM1 might explain partly the strong synergism between these two oncogenes in tumorigenesis. Mediates survival signaling through phosphorylation of BAD, which induces release of the anti-apoptotic protein Bcl-X(L)/BCL2L1. Phosphorylation of MAP3K5, an other proapoptotic protein, by PIM1, significantly decreases MAP3K5 kinase activity and inhibits MAP3K5-mediated phosphorylation of JNK and JNK/p38MAPK subsequently reducing caspase-3 activation and cell apoptosis. Stimulates cell cycle progression at the G1-S and G2-M transitions by phosphorylation of CDC25A and CDC25C. Phosphorylation of CDKN1A, a regulator of cell cycle progression at G1, results in the relocation of CDKN1A to the cytoplasm and enhanced CDKN1A protein stability. Promote cell cycle progression and tumorigenesis by down-regulating expression of a regulator of cell cycle progression, CDKN1B, at both transcriptional and post-translational levels. Phosphorylation of CDKN1B,induces 14-3-3-proteins binding, nuclear export and proteasome-dependent degradation. May affect the structure or silencing of chromatin by phosphorylating HP1 gamma/CBX3. Acts also as a regulator of homing and migration of bone marrow cells involving functional interaction with the CXCL12-CXCR4 signaling axis.<ref>PMID:1825810</ref><ref>PMID:10664448</ref><ref>PMID:12431783</ref><ref>PMID:15528381</ref><ref>PMID:16356754</ref><ref>PMID:18593906</ref><ref>PMID:19749799</ref>

	==About this Structure==		==About this Structure==
-	~~3JXW~~ is a 1 chain structure of 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=3JXW OCA].	+	[[3jxw]] 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=3JXW OCA].
		+
		+	==Reference==
		+	<references group="xtra"/><references/>
	[[Category: Homo sapiens]]		[[Category: Homo sapiens]]
	[[Category: Non-specific serine/threonine protein kinase]]		[[Category: Non-specific serine/threonine protein kinase]]
Line 21:		Line 16:
	[[Category: Atp-binding]]		[[Category: Atp-binding]]
	[[Category: Cell membrane]]		[[Category: Cell membrane]]
-	[[Category: Cytoplasm]]
	[[Category: Kinase]]		[[Category: Kinase]]
	[[Category: Manganese]]		[[Category: Manganese]]
Line 30:		Line 24:
	[[Category: Phosphoprotein]]		[[Category: Phosphoprotein]]
	[[Category: Pim-1]]		[[Category: Pim-1]]
-	[[Category: Polymorphism]]
	[[Category: Proto-oncogene]]		[[Category: Proto-oncogene]]
	[[Category: Serine/threonine-protein kinase]]		[[Category: Serine/threonine-protein kinase]]
	[[Category: Transferase]]		[[Category: Transferase]]
-
-	''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Wed Nov 11 22:34:39 2009''

OCA at 20:34, 11 November 2009

2009-11-11T20:34:42Z

←Older revision		Revision as of 20:34, 11 November 2009
Line 1:		Line 1:
-	~~'''Unreleased structure'''~~	+	{{Seed}}
		+	[[Image:3jxw.jpg\|left\|200px]]

-	The ~~entry 3jxw~~ is ~~ON HOLD~~	+	<!--
		+	The line below this paragraph, containing "STRUCTURE_3jxw", creates the "Structure Box" on the page.
		+	You may change the PDB parameter (which sets the PDB file loaded into the applet)
		+	or the SCENE parameter (which sets the initial scene displayed when the page is loaded),
		+	or leave the SCENE parameter empty for the default display.
		+	-->
		+	{{STRUCTURE_3jxw\| PDB=3jxw \| SCENE= }}

-	~~Authors: Stoll~~, ~~V.S.~~	+	===Discovery of 3H-benzo[4,5]thieno[3,2-d]pyrimidin-4-ones as Potent, Highly Selective and Orally Bioavailable Pim Kinases Inhibitors===

-	Description: Discovery of 3H-benzo[4,5]thieno[3,2-d]pyrimidin-4-ones as Potent, Highly Selective and Orally Bioavailable Pim Kinases Inhibitors

-	''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Wed ~~Sep 30 09~~:00:58 2009''	+	==About this Structure==
		+	3JXW is a 1 chain structure of 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=3JXW OCA].
		+	[[Category: Homo sapiens]]
		+	[[Category: Non-specific serine/threonine protein kinase]]
		+	[[Category: Stoll, V S.]]
		+	[[Category: Alternative initiation]]
		+	[[Category: Atp-binding]]
		+	[[Category: Cell membrane]]
		+	[[Category: Cytoplasm]]
		+	[[Category: Kinase]]
		+	[[Category: Manganese]]
		+	[[Category: Membrane]]
		+	[[Category: Metal-binding]]
		+	[[Category: Nucleotide-binding]]
		+	[[Category: Nucleus]]
		+	[[Category: Phosphoprotein]]
		+	[[Category: Pim-1]]
		+	[[Category: Polymorphism]]
		+	[[Category: Proto-oncogene]]
		+	[[Category: Serine/threonine-protein kinase]]
		+	[[Category: Transferase]]
		+
		+	''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Wed Nov 11 22:34:39 2009''

OCA: New page: '''Unreleased structure''' The entry 3jxw is ON HOLD Authors: Stoll, V.S. Description: Discovery of 3H-benzo[4,5]thieno[3,2-d]pyrimidin-4-ones as Potent, Highly Selective and Orally Bi...

2009-09-30T07:00:58Z

New page: '''Unreleased structure''' The entry 3jxw is ON HOLD Authors: Stoll, V.S. Description: Discovery of 3H-benzo[4,5]thieno[3,2-d]pyrimidin-4-ones as Potent, Highly Selective and Orally Bi...

New page

'''Unreleased structure'''

The entry 3jxw is ON HOLD

Authors: Stoll, V.S.

Description: Discovery of 3H-benzo[4,5]thieno[3,2-d]pyrimidin-4-ones as Potent, Highly Selective and Orally Bioavailable Pim Kinases Inhibitors

''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Wed Sep 30 09:00:58 2009''