5v80 - Revision history

OCA at 14:31, 6 March 2024

2024-03-06T14:31:34Z

←Older revision		Revision as of 14:31, 6 March 2024
Line 3:		Line 3:
	<StructureSection load='5v80' size='340' side='right'caption='[[5v80]], [[Resolution\|resolution]] 2.25Å' scene=''>		<StructureSection load='5v80' size='340' side='right'caption='[[5v80]], [[Resolution\|resolution]] 2.25Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
-	<table><tr><td colspan='2'>[[5v80]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5V80 OCA]. For a <b>guided tour on the structure components</b> use [~~http~~://proteopedia.org/fgij/fg.htm?mol=5V80 FirstGlance]. <br>	+	<table><tr><td colspan='2'>[[5v80]] 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=5V80 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5V80 FirstGlance]. <br>
-	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=971:1-methyl-4-{3-[6-(piperazin-1-yl)pyridin-2-yl]-1H-pyrazolo[3,4-c]pyridin-5-yl}piperazin-2-one'>971</scene>, <scene name='pdbligand=PO4:PHOSPHATE+ION'>PO4</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]] 2.252Å</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='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=971:1-methyl-4-{3-[6-(piperazin-1-yl)pyridin-2-yl]-1H-pyrazolo[3,4-c]pyridin-5-yl}piperazin-2-one'>971</scene>, <scene name='pdbligand=PO4:PHOSPHATE+ION'>PO4</scene></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=5v80 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5v80 OCA], [~~http~~://pdbe.org/5v80 PDBe], [~~http~~://www.rcsb.org/pdb/explore.do?structureId=5v80 RCSB], [~~http~~://www.ebi.ac.uk/pdbsum/5v80 PDBsum], [~~http~~://prosat.h-its.org/prosat/prosatexe?pdbcode=5v80 ProSAT]</span></td></tr>	+	<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=5v80 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5v80 OCA], [https://pdbe.org/5v80 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5v80 RCSB], [https://www.ebi.ac.uk/pdbsum/5v80 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5v80 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;">~~	+
-	~~== Publication Abstract from PubMed ==~~	+
-	Pim kinases have been identified as promising therapeutic targets for hematologic-oncology indications, including multiple myeloma and certain leukemia. Here, we describe our continued efforts in optimizing a lead series by improving bioavailability while maintaining high inhibitory potency against all three Pim kinase isoforms. The discovery of extensive intestinal metabolism and major metabolites helped refine our design strategy, and we observed that optimizing the pharmacokinetic properties first and potency second was a more successful approach than the reverse. In the resulting work, novel analogs such as 20 (GNE-955) were discovered bearing 5-azaindazole core with noncanonical hydrogen bonding to the hinge.	+
-		+
-	Discovery of 5-Azaindazole (GNE-955) as a Potent Pan-Pim Inhibitor with Optimized Bioavailability.,Wang X, Kolesnikov A, Tay S, Chan G, Chao Q, Do S, Drummond J, Ebens AJ, Liu N, Ly J, Harstad E, Hu H, Moffat J, Munugalavadla V, Murray J, Slaga D, Tsui V, Volgraf M, Wallweber H, Chang JH J Med Chem. 2017 May 5. doi: 10.1021/acs.jmedchem.7b00418. PMID:28445037<ref>PMID:28445037</ref>	+
-		+
-	~~From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>~~	+
-	~~</div>~~	+
-	~~<div class="pdbe-citations 5v80" style="background-color:#fffaf0;"></div~~>	+

	==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]]		*[[Serine/threonine protein kinase 3D structures\|Serine/threonine protein kinase 3D structures]]
		+	*[[3D structures of pim-1\|3D structures of pim-1]]
	== References ==		== References ==
	<references/>		<references/>
	__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: Pim1]]~~	+
-	~~[[Category: Sbdd]]~~	+
-	~~[[Category: Transferase-inhibitor complex~~]]	+

OCA at 08:32, 30 September 2020

2020-09-30T08:32:17Z

←Older revision		Revision as of 08:32, 30 September 2020
Line 1:		Line 1:

	==PIM1 kinase in complex with Cpd1 (1-methyl-4-(3-(6-(piperazin-1-yl)pyridin-2-yl)-1H-pyrazolo[3,4-c]pyridin-5-yl)piperazin-2-one)==		==PIM1 kinase in complex with Cpd1 (1-methyl-4-(3-(6-(piperazin-1-yl)pyridin-2-yl)-1H-pyrazolo[3,4-c]pyridin-5-yl)piperazin-2-one)==
-	<StructureSection load='5v80' size='340' side='right' caption='[[5v80]], [[Resolution\|resolution]] 2.25Å' scene=''>	+	<StructureSection load='5v80' size='340' side='right'caption='[[5v80]], [[Resolution\|resolution]] 2.25Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
-	<table><tr><td colspan='2'>[[5v80]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5V80 OCA]. For a <b>guided tour on the structure components</b> use [http://~~oca~~.~~weizmann.ac.il/oca-docs~~/fgij/fg.htm?mol=5V80 FirstGlance]. <br>	+	<table><tr><td colspan='2'>[[5v80]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5V80 OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=5V80 FirstGlance]. <br>
-	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=971:1-methyl-4-{3-[6-(piperazin-1-yl)pyridin-2-yl]-1H-pyrazolo[3,4-c]pyridin-5-yl}piperazin-2-one'>971</scene>, <scene name='pdbligand=PO4:PHOSPHATE+ION'>PO4</scene></td></tr>	+	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=971:1-methyl-4-{3-[6-(piperazin-1-yl)pyridin-2-yl]-1H-pyrazolo[3,4-c]pyridin-5-yl}piperazin-2-one'>971</scene>, <scene name='pdbligand=PO4:PHOSPHATE+ION'>PO4</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='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=5v80 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5v80 OCA], [http://pdbe.org/5v80 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5v80 RCSB], [http://www.ebi.ac.uk/pdbsum/5v80 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5v80 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=5v80 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5v80 OCA], [http://pdbe.org/5v80 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5v80 RCSB], [http://www.ebi.ac.uk/pdbsum/5v80 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5v80 ProSAT]</span></td></tr>
	</table>		</table>
	== Function ==		== Function ==
Line 19:		Line 19:
	</div>		</div>
	<div class="pdbe-citations 5v80" style="background-color:#fffaf0;"></div>		<div class="pdbe-citations 5v80" style="background-color:#fffaf0;"></div>
		+
		+	==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]]
	== References ==		== References ==
	<references/>		<references/>
	__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 05:37, 18 April 2018

2018-04-18T05:37:51Z

←Older revision		Revision as of 05:37, 18 April 2018
Line 1:		Line 1:
-	'''Unreleased structure'''

-	~~The entry~~ 5v80 is ~~ON HOLD~~	+	==PIM1 kinase in complex with Cpd1 (1-methyl-4-(3-(6-(piperazin-1-yl)pyridin-2-yl)-1H-pyrazolo[3,4-c]pyridin-5-yl)piperazin-2-one)==
		+	<StructureSection load='5v80' size='340' side='right' caption='[[5v80]], [[Resolution\|resolution]] 2.25Å' scene=''>
		+	== Structural highlights ==
		+	<table><tr><td colspan='2'>[[5v80]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5V80 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5V80 FirstGlance]. <br>
		+	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=971:1-methyl-4-{3-[6-(piperazin-1-yl)pyridin-2-yl]-1H-pyrazolo[3,4-c]pyridin-5-yl}piperazin-2-one'>971</scene>, <scene name='pdbligand=PO4:PHOSPHATE+ION'>PO4</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'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5v80 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5v80 OCA], [http://pdbe.org/5v80 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5v80 RCSB], [http://www.ebi.ac.uk/pdbsum/5v80 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5v80 ProSAT]</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 kinases have been identified as promising therapeutic targets for hematologic-oncology indications, including multiple myeloma and certain leukemia. Here, we describe our continued efforts in optimizing a lead series by improving bioavailability while maintaining high inhibitory potency against all three Pim kinase isoforms. The discovery of extensive intestinal metabolism and major metabolites helped refine our design strategy, and we observed that optimizing the pharmacokinetic properties first and potency second was a more successful approach than the reverse. In the resulting work, novel analogs such as 20 (GNE-955) were discovered bearing 5-azaindazole core with noncanonical hydrogen bonding to the hinge.

-	~~Authors: Murray~~, J.M., Wallweber, H.	+	Discovery of 5-Azaindazole (GNE-955) as a Potent Pan-Pim Inhibitor with Optimized Bioavailability.,Wang X, Kolesnikov A, Tay S, Chan G, Chao Q, Do S, Drummond J, Ebens AJ, Liu N, Ly J, Harstad E, Hu H, Moffat J, Munugalavadla V, Murray J, Slaga D, Tsui V, Volgraf M, Wallweber H, Chang JH J Med Chem. 2017 May 5. doi: 10.1021/acs.jmedchem.7b00418. PMID:28445037<ref>PMID:28445037</ref>

-	~~Description: PIM1 kinase in complex with Cpd1 (1-methyl-4-(3-(6-(piperazin-1-yl)pyridin-2-yl)-1H-pyrazolo[3~~,4-~~c]pyridin~~-~~5-yl)piperazin-2-one)~~	+	From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
-	[[Category: ~~Unreleased Structures~~]]	+	</div>
-	[[Category: Murray, J.M]]	+	<div class="pdbe-citations 5v80" style="background-color:#fffaf0;"></div>
		+	== References ==
		+	<references/>
		+	__TOC__
		+	</StructureSection>
		+	[[Category: Non-specific serine/threonine protein kinase]]
		+	[[Category: Murray, J M]]
	[[Category: Wallweber, H]]		[[Category: Wallweber, H]]
		+	[[Category: Pim1]]
		+	[[Category: Sbdd]]
		+	[[Category: Transferase-inhibitor complex]]

OCA: Protected "5v80" [edit=sysop:move=sysop]

2017-04-05T11:42:50Z

Protected "5v80" [edit=sysop:move=sysop]

←Older revision

Revision as of 11:42, 5 April 2017

OCA: New page: '''Unreleased structure''' The entry 5v80 is ON HOLD Authors: Murray, J.M., Wallweber, H. Description: PIM1 kinase in complex with Cpd1 (1-methyl-4-(3-(6-(piperazin-1-yl)pyridin-2-yl)-...

2017-04-05T11:42:49Z

New page: '''Unreleased structure''' The entry 5v80 is ON HOLD Authors: Murray, J.M., Wallweber, H. Description: PIM1 kinase in complex with Cpd1 (1-methyl-4-(3-(6-(piperazin-1-yl)pyridin-2-yl)-...

New page

'''Unreleased structure'''

The entry 5v80 is ON HOLD

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

Description: PIM1 kinase in complex with Cpd1 (1-methyl-4-(3-(6-(piperazin-1-yl)pyridin-2-yl)-1H-pyrazolo[3,4-c]pyridin-5-yl)piperazin-2-one)
[[Category: Unreleased Structures]]
[[Category: Murray, J.M]]
[[Category: Wallweber, H]]