5dia - Revision history

OCA at 12:24, 6 March 2024

OCA — Wed, 06 Mar 2024 12:24:46 GMT

←Older revision		Revision as of 12:24, 6 March 2024
Line 10:		Line 10:
	== Function ==		== Function ==
	[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>		[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>
-	<div style="background-color:#fffaf0;">
-	== Publication Abstract from PubMed ==
-	Pim kinase inhibitors are promising cancer therapeutics. Pim-2, among the three Pim isoforms, plays a critical role in multiple myeloma yet inhibition of Pim-2 is challenging due to its high affinity for ATP. A co-crystal structure of a screening hit 1 bound to Pim-1 kinase revealed the key binding interactions of its indazole core within the ATP binding site. Screening of analogous core fragments afforded 1H-pyrazolo[3,4-c]pyridine (6-azaindazole) as a core for the development of pan-Pim inhibitors. Fragment and structure based drug design led to identification of the series with picomolar biochemical potency against all three Pim isoforms. Desirable cellular potency was also achieved.

-	Discovery of 3,5-substituted 6-azaindazoles as potent pan-Pim inhibitors.,Hu H, Wang X, Chan GK, Chang JH, Do S, Drummond J, Ebens A, Lee W, Ly J, Lyssikatos JP, Murray J, Moffat JG, Chao Q, Tsui V, Wallweber H, Kolesnikov A Bioorg Med Chem Lett. 2015 Nov 15;25(22):5258-64. doi:, 10.1016/j.bmcl.2015.09.052. Epub 2015 Sep 30. PMID:26459208<ref>PMID:26459208</ref>	+	==See Also==
-		+	*[[Serine/threonine protein kinase 3D structures\|Serine/threonine protein kinase 3D structures]]
-	~~From MEDLINE®~~/~~PubMed®, a database of the U.S. National Library of Medicine.<br>~~	+
-	~~</div>~~	+
-	~~<div class="pdbe-citations 5dia" style="background-color:#fffaf0;"><~~/~~div>~~	+
	== References ==		== References ==
	<references/>		<references/>

OCA at 21:42, 28 June 2023

OCA — Wed, 28 Jun 2023 21:42:46 GMT

←Older revision		Revision as of 21:42, 28 June 2023
Line 3:		Line 3:
	<StructureSection load='5dia' size='340' side='right'caption='[[5dia]], [[Resolution\|resolution]] 1.96Å' scene=''>		<StructureSection load='5dia' size='340' side='right'caption='[[5dia]], [[Resolution\|resolution]] 1.96Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
-	<table><tr><td colspan='2'>[[5dia]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5DIA OCA]. For a <b>guided tour on the structure components</b> use [~~http~~://proteopedia.org/fgij/fg.htm?mol=5DIA FirstGlance]. <br>	+	<table><tr><td colspan='2'>[[5dia]] 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=5DIA OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5DIA FirstGlance]. <br>
-	</td></tr><tr id='~~ligand~~'><td class="sblockLbl"><b>[[~~Ligand~~\|~~Ligands~~:]]</b></td><td class="sblockDat" id="~~ligandDat~~">~~<scene name='pdbligand=5E6:(1S~~,~~3S)-N-{6-~~[~~5-(PYRIDIN-3-YL)-1H-PYRAZOLO~~[~~3,4-C~~]~~PYRIDIN-3-YL~~]~~PYRIDIN-2-YL}CYCLOHEXANE-~~1~~,3-DIAMINE'>5E6</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]] 1.964Å</td></tr>
-	<tr id='~~related~~'><td class="sblockLbl"><b>[[~~Related_structure~~\|~~Related~~:]]</b></td><td class="sblockDat"~~>[[5dgz\|5dgz]], [[5dhj\|5dhj]]</td></tr>~~	+	<tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=5E6:(1S,3S)-N-{6-[5-(PYRIDIN-3-YL)-1H-PYRAZOLO[3,4-C]PYRIDIN-3-YL]PYRIDIN-2-YL}CYCLOHEXANE-1,3-DIAMINE'>5E6</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=5dia FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5dia OCA], [https://pdbe.org/5dia PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5dia RCSB], [https://www.ebi.ac.uk/pdbsum/5dia PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5dia 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=5dia FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5dia OCA], [~~http~~://pdbe.org/5dia PDBe], [~~http~~://www.rcsb.org/pdb/explore.do?structureId=5dia RCSB], [~~http~~://www.ebi.ac.uk/pdbsum/5dia PDBsum], [~~http~~://prosat.h-its.org/prosat/prosatexe?pdbcode=5dia 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>
	<div style="background-color:#fffaf0;">		<div style="background-color:#fffaf0;">
	== Publication Abstract from PubMed ==		== Publication Abstract from PubMed ==
Line 24:		Line 23:
	__TOC__		__TOC__
	</StructureSection>		</StructureSection>
		+	[[Category: Homo sapiens]]
	[[Category: Large Structures]]		[[Category: Large Structures]]
-	~~[[Category: Non-specific serine/threonine protein kinase]]~~	+	[[Category: Murray JM]]
-	[[Category: Murray~~, J M~~]]	+	[[Category: Wallweber H]]
-	[[Category: Wallweber, H]]	+
-	~~[[Category: Atp-competitive]]~~	+
-	~~[[Category: Kinase]]~~	+
-	~~[[Category: Pim-1]]~~	+
-	~~[[Category: Structure-based drug design]]~~	+
-	~~[[Category: Transferase-transferase inhibitor complex~~]]	+

OCA at 08:04, 8 April 2020

OCA — Wed, 08 Apr 2020 08:04:32 GMT

←Older revision		Revision as of 08:04, 8 April 2020
Line 1:		Line 1:

	==PIM1 in complex with Cpd36 ((1S,3S)-N1-(6-(5-(pyridin-3-yl)-1H-pyrazolo[3,4-c]pyridin-3-yl)pyridin-2-yl)cyclohexane-1,3-diamine)==		==PIM1 in complex with Cpd36 ((1S,3S)-N1-(6-(5-(pyridin-3-yl)-1H-pyrazolo[3,4-c]pyridin-3-yl)pyridin-2-yl)cyclohexane-1,3-diamine)==
-	<StructureSection load='5dia' size='340' side='right' caption='[[5dia]], [[Resolution\|resolution]] 1.96Å' scene=''>	+	<StructureSection load='5dia' size='340' side='right'caption='[[5dia]], [[Resolution\|resolution]] 1.96Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
-	<table><tr><td colspan='2'>[[5dia]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5DIA OCA]. For a <b>guided tour on the structure components</b> use [http://~~oca~~.~~weizmann.ac.il/oca-docs~~/fgij/fg.htm?mol=5DIA FirstGlance]. <br>	+	<table><tr><td colspan='2'>[[5dia]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5DIA OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=5DIA FirstGlance]. <br>
-	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=5E6:(1S,3S)-N-{6-[5-(PYRIDIN-3-YL)-1H-PYRAZOLO[3,4-C]PYRIDIN-3-YL]PYRIDIN-2-YL}CYCLOHEXANE-1,3-DIAMINE'>5E6</scene></td></tr>	+	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=5E6:(1S,3S)-N-{6-[5-(PYRIDIN-3-YL)-1H-PYRAZOLO[3,4-C]PYRIDIN-3-YL]PYRIDIN-2-YL}CYCLOHEXANE-1,3-DIAMINE'>5E6</scene></td></tr>
	<tr id='related'><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat">[[5dgz\|5dgz]], [[5dhj\|5dhj]]</td></tr>		<tr id='related'><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat">[[5dgz\|5dgz]], [[5dhj\|5dhj]]</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=5dia FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5dia OCA], [http://pdbe.org/5dia PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5dia RCSB], [http://www.ebi.ac.uk/pdbsum/5dia PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5dia 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=5dia FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5dia OCA], [http://pdbe.org/5dia PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5dia RCSB], [http://www.ebi.ac.uk/pdbsum/5dia PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5dia ProSAT]</span></td></tr>
	</table>		</table>
	== Function ==		== Function ==
Line 24:		Line 24:
	__TOC__		__TOC__
	</StructureSection>		</StructureSection>
		+	[[Category: Large Structures]]
	[[Category: Non-specific serine/threonine protein kinase]]		[[Category: Non-specific serine/threonine protein kinase]]
	[[Category: Murray, J M]]		[[Category: Murray, J M]]

OCA at 16:55, 18 August 2017

OCA — Fri, 18 Aug 2017 16:55:23 GMT

←Older revision		Revision as of 16:55, 18 August 2017
Line 1:		Line 1:
		+
	==PIM1 in complex with Cpd36 ((1S,3S)-N1-(6-(5-(pyridin-3-yl)-1H-pyrazolo[3,4-c]pyridin-3-yl)pyridin-2-yl)cyclohexane-1,3-diamine)==		==PIM1 in complex with Cpd36 ((1S,3S)-N1-(6-(5-(pyridin-3-yl)-1H-pyrazolo[3,4-c]pyridin-3-yl)pyridin-2-yl)cyclohexane-1,3-diamine)==
	<StructureSection load='5dia' size='340' side='right' caption='[[5dia]], [[Resolution\|resolution]] 1.96Å' scene=''>		<StructureSection load='5dia' size='340' side='right' caption='[[5dia]], [[Resolution\|resolution]] 1.96Å' scene=''>
Line 6:		Line 7:
	<tr id='related'><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat">[[5dgz\|5dgz]], [[5dhj\|5dhj]]</td></tr>		<tr id='related'><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat">[[5dgz\|5dgz]], [[5dhj\|5dhj]]</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=5dia FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5dia OCA], [http://pdbe.org/5dia PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5dia RCSB], [http://www.ebi.ac.uk/pdbsum/5dia 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=5dia FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5dia OCA], [http://pdbe.org/5dia PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5dia RCSB], [http://www.ebi.ac.uk/pdbsum/5dia PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5dia ProSAT]</span></td></tr>
	</table>		</table>
	== Function ==		== Function ==

OCA at 19:38, 30 November 2015

OCA — Mon, 30 Nov 2015 19:38:58 GMT

←Older revision		Revision as of 19:38, 30 November 2015
Line 1:		Line 1:
-	'''~~Unreleased~~ structure'''	+	==PIM1 in complex with Cpd36 ((1S,3S)-N1-(6-(5-(pyridin-3-yl)-1H-pyrazolo[3,4-c]pyridin-3-yl)pyridin-2-yl)cyclohexane-1,3-diamine)==
		+	<StructureSection load='5dia' size='340' side='right' caption='[[5dia]], [[Resolution\|resolution]] 1.96Å' scene=''>
		+	== Structural highlights ==
		+	<table><tr><td colspan='2'>[[5dia]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5DIA OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5DIA FirstGlance]. <br>
		+	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=5E6:(1S,3S)-N-{6-[5-(PYRIDIN-3-YL)-1H-PYRAZOLO[3,4-C]PYRIDIN-3-YL]PYRIDIN-2-YL}CYCLOHEXANE-1,3-DIAMINE'>5E6</scene></td></tr>
		+	<tr id='related'><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat">[[5dgz\|5dgz]], [[5dhj\|5dhj]]</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=5dia FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5dia OCA], [http://pdbe.org/5dia PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5dia RCSB], [http://www.ebi.ac.uk/pdbsum/5dia PDBsum]</span></td></tr>
		+	</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>
		+	<div style="background-color:#fffaf0;">
		+	== Publication Abstract from PubMed ==
		+	Pim kinase inhibitors are promising cancer therapeutics. Pim-2, among the three Pim isoforms, plays a critical role in multiple myeloma yet inhibition of Pim-2 is challenging due to its high affinity for ATP. A co-crystal structure of a screening hit 1 bound to Pim-1 kinase revealed the key binding interactions of its indazole core within the ATP binding site. Screening of analogous core fragments afforded 1H-pyrazolo[3,4-c]pyridine (6-azaindazole) as a core for the development of pan-Pim inhibitors. Fragment and structure based drug design led to identification of the series with picomolar biochemical potency against all three Pim isoforms. Desirable cellular potency was also achieved.

-	~~The entry 5dia is ON HOLD~~	+	Discovery of 3,5-substituted 6-azaindazoles as potent pan-Pim inhibitors.,Hu H, Wang X, Chan GK, Chang JH, Do S, Drummond J, Ebens A, Lee W, Ly J, Lyssikatos JP, Murray J, Moffat JG, Chao Q, Tsui V, Wallweber H, Kolesnikov A Bioorg Med Chem Lett. 2015 Nov 15;25(22):5258-64. doi:, 10.1016/j.bmcl.2015.09.052. Epub 2015 Sep 30. PMID:26459208<ref>PMID:26459208</ref>

-	~~Authors: Murray~~, J.M.~~, Wallweber, H~~.	+	From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
-		+	</div>
-	~~Description: PIM1 in complex with Cpd36 ((1S,3S)~~-N1-~~(6-(5-(pyridin-3-yl)-1H-pyrazolo[3,4-c]pyridin-3-yl)pyridin-2-yl)cyclohexane-1,3-diamine)~~	+	<div class="pdbe-citations 5dia" style="background-color:#fffaf0;"></div>
-	[[Category: ~~Unreleased Structures~~]]	+	== References ==
-	[[Category: Murray, J.M]]	+	<references/>
		+	__TOC__
		+	</StructureSection>
		+	[[Category: Non-specific serine/threonine protein kinase]]
		+	[[Category: Murray, J M]]
	[[Category: Wallweber, H]]		[[Category: Wallweber, H]]
		+	[[Category: Atp-competitive]]
		+	[[Category: Kinase]]
		+	[[Category: Pim-1]]
		+	[[Category: Structure-based drug design]]
		+	[[Category: Transferase-transferase inhibitor complex]]

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

OCA — Wed, 09 Sep 2015 10:15:11 GMT

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

←Older revision

Revision as of 10:15, 9 September 2015

OCA: New page: '''Unreleased structure''' The entry 5dia is ON HOLD Authors: Murray, J.M., Wallweber, H. Description: PIM1 in complex with Cpd36 ((1S,3S)-N1-(6-(5-(pyridin-3-yl)-1H-pyrazolo[3,4-c]pyr...

OCA — Wed, 09 Sep 2015 10:15:09 GMT

New page: '''Unreleased structure''' The entry 5dia is ON HOLD Authors: Murray, J.M., Wallweber, H. Description: PIM1 in complex with Cpd36 ((1S,3S)-N1-(6-(5-(pyridin-3-yl)-1H-pyrazolo[3,4-c]pyr...

New page

'''Unreleased structure'''

The entry 5dia is ON HOLD

Authors: Murray, J.M., Wallweber, H.

Description: PIM1 in complex with Cpd36 ((1S,3S)-N1-(6-(5-(pyridin-3-yl)-1H-pyrazolo[3,4-c]pyridin-3-yl)pyridin-2-yl)cyclohexane-1,3-diamine)
[[Category: Unreleased Structures]]
[[Category: Murray, J.M]]
[[Category: Wallweber, H]]