5fgk - Revision history

OCA at 06:50, 19 July 2023

2023-07-19T06:50:18Z

←Older revision		Revision as of 06:50, 19 July 2023
Line 3:		Line 3:
	<StructureSection load='5fgk' size='340' side='right'caption='[[5fgk]], [[Resolution\|resolution]] 2.36Å' scene=''>		<StructureSection load='5fgk' size='340' side='right'caption='[[5fgk]], [[Resolution\|resolution]] 2.36Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
-	<table><tr><td colspan='2'>[[5fgk]] is a 2 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=5FGK OCA]. For a <b>guided tour on the structure components</b> use [~~http~~://proteopedia.org/fgij/fg.htm?mol=5FGK FirstGlance]. <br>	+	<table><tr><td colspan='2'>[[5fgk]] is a 2 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=5FGK OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5FGK FirstGlance]. <br>
-	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=5XG:8-[3-(3-AZANYL-2~{H}-INDAZOL-6-YL)-5-CHLORANYL-PYRIDIN-4-YL]-2,8-DIAZASPIRO[4.5]DECAN-1-ONE'>5XG</scene>, <scene name='pdbligand=DMS:DIMETHYL+SULFOXIDE'>DMS</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=FMT:FORMIC+ACID'>FMT</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]] 2.36Å</td></tr>
-	<tr id='gene'><td class="sblockLbl"><b>[[Gene\|Gene:]]</b></td><td class="sblockDat">CDK8 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN]), CCNC ([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=5XG:8-[3-(3-AZANYL-2~{H}-INDAZOL-6-YL)-5-CHLORANYL-PYRIDIN-4-YL]-2,8-DIAZASPIRO[4.5]DECAN-1-ONE'>5XG</scene>, <scene name='pdbligand=DMS:DIMETHYL+SULFOXIDE'>DMS</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=FMT:FORMIC+ACID'>FMT</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=5fgk FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5fgk OCA], [~~http~~://pdbe.org/5fgk PDBe], [~~http~~://www.rcsb.org/pdb/explore.do?structureId=5fgk RCSB], [~~http~~://www.ebi.ac.uk/pdbsum/5fgk PDBsum], [~~http~~://prosat.h-its.org/prosat/prosatexe?pdbcode=5fgk 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=5fgk FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5fgk OCA], [https://pdbe.org/5fgk PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5fgk RCSB], [https://www.ebi.ac.uk/pdbsum/5fgk PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5fgk ProSAT]</span></td></tr>
	</table>		</table>
	== Function ==		== Function ==
-	[~~[http~~://www.uniprot.org/uniprot/CDK8_HUMAN CDK8_HUMAN]] Component of the Mediator complex, a coactivator involved in regulated gene transcription of nearly all RNA polymerase II-dependent genes. Mediator functions as a bridge to convey information from gene-specific regulatory proteins to the basal RNA polymerase II transcription machinery. Mediator is recruited to promoters by direct interactions with regulatory proteins and serves as a scaffold for the assembly of a functional preinitiation complex with RNA polymerase II and the general transcription factors. Phosphorylates the CTD (C-terminal domain) of the large subunit of RNA polymerase II (RNAp II), which may inhibit the formation of a transcription initiation complex. Phosphorylates CCNH leading to down-regulation of the TFIIH complex and transcriptional repression. Recruited through interaction with MAML1 to hyperphosphorylate the intracellular domain of NOTCH, leading to its degradation.<ref>PMID:10993082</ref> <ref>PMID:15546612</ref> [[http://www.uniprot.org/uniprot/CCNC_HUMAN CCNC_HUMAN]] Component of the Mediator complex, a coactivator involved in regulated gene transcription of nearly all RNA polymerase II-dependent genes. Mediator functions as a bridge to convey information from gene-specific regulatory proteins to the basal RNA polymerase II transcription machinery. Mediator is recruited to promoters by direct interactions with regulatory proteins and serves as a scaffold for the assembly of a functional preinitiation complex with RNA polymerase II and the general transcription factors. Binds to and activates cyclin-dependent kinase CDK8 that phosphorylates the CTD (C-terminal domain) of the large subunit of RNA polymerase II (RNAp II), which may inhibit the formation of a transcription initiation complex.<ref>PMID:8700522</ref> <ref>PMID:16595664</ref>	+	[https://www.uniprot.org/uniprot/CDK8_HUMAN CDK8_HUMAN] Component of the Mediator complex, a coactivator involved in regulated gene transcription of nearly all RNA polymerase II-dependent genes. Mediator functions as a bridge to convey information from gene-specific regulatory proteins to the basal RNA polymerase II transcription machinery. Mediator is recruited to promoters by direct interactions with regulatory proteins and serves as a scaffold for the assembly of a functional preinitiation complex with RNA polymerase II and the general transcription factors. Phosphorylates the CTD (C-terminal domain) of the large subunit of RNA polymerase II (RNAp II), which may inhibit the formation of a transcription initiation complex. Phosphorylates CCNH leading to down-regulation of the TFIIH complex and transcriptional repression. Recruited through interaction with MAML1 to hyperphosphorylate the intracellular domain of NOTCH, leading to its degradation.<ref>PMID:10993082</ref> <ref>PMID:15546612</ref>
	<div style="background-color:#fffaf0;">		<div style="background-color:#fffaf0;">
	== Publication Abstract from PubMed ==		== Publication Abstract from PubMed ==
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	__TOC__		__TOC__
	</StructureSection>		</StructureSection>
-	[[Category: ~~Human~~]]	+	[[Category: Homo sapiens]]
	[[Category: Large Structures]]		[[Category: Large Structures]]
-	[[Category: Blagg, J]]	+	[[Category: Blagg J]]
-	[[Category: Mallinger, A]]	+	[[Category: Mallinger A]]
-	[[Category: Musil, D]]	+	[[Category: Musil D]]
-	~~[[Category: Cdk8 kinase / cyclin c]]~~	+
-	~~[[Category: Transferase~~]]	+

OCA at 07:18, 6 May 2020

2020-05-06T07:18:33Z

←Older revision		Revision as of 07:18, 6 May 2020
Line 1:		Line 1:

	==CDK8-CYCC IN COMPLEX WITH 8-[3-(3-Amino-1H-indazol-6-yl)-5-chloro- pyridine-4-yl]-2,8-diaza-spiro[4.5]decan-1-one==		==CDK8-CYCC IN COMPLEX WITH 8-[3-(3-Amino-1H-indazol-6-yl)-5-chloro- pyridine-4-yl]-2,8-diaza-spiro[4.5]decan-1-one==
-	<StructureSection load='5fgk' size='340' side='right' caption='[[5fgk]], [[Resolution\|resolution]] 2.36Å' scene=''>	+	<StructureSection load='5fgk' size='340' side='right'caption='[[5fgk]], [[Resolution\|resolution]] 2.36Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
-	<table><tr><td colspan='2'>[[5fgk]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5FGK OCA]. For a <b>guided tour on the structure components</b> use [http://~~oca~~.~~weizmann.ac.il/oca-docs~~/fgij/fg.htm?mol=5FGK FirstGlance]. <br>	+	<table><tr><td colspan='2'>[[5fgk]] is a 2 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=5FGK OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=5FGK FirstGlance]. <br>
-	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=5XG:8-[3-(3-AZANYL-2~{H}-INDAZOL-6-YL)-5-CHLORANYL-PYRIDIN-4-YL]-2,8-DIAZASPIRO[4.5]DECAN-1-ONE'>5XG</scene>, <scene name='pdbligand=DMS:DIMETHYL+SULFOXIDE'>DMS</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=FMT:FORMIC+ACID'>FMT</scene></td></tr>	+	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=5XG:8-[3-(3-AZANYL-2~{H}-INDAZOL-6-YL)-5-CHLORANYL-PYRIDIN-4-YL]-2,8-DIAZASPIRO[4.5]DECAN-1-ONE'>5XG</scene>, <scene name='pdbligand=DMS:DIMETHYL+SULFOXIDE'>DMS</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=FMT:FORMIC+ACID'>FMT</scene></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=5fgk FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5fgk OCA], [http://pdbe.org/5fgk PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5fgk RCSB], [http://www.ebi.ac.uk/pdbsum/5fgk PDBsum]</span></td></tr>	+	<tr id='gene'><td class="sblockLbl"><b>[[Gene\|Gene:]]</b></td><td class="sblockDat">CDK8 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN]), CCNC ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</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=5fgk FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5fgk OCA], [http://pdbe.org/5fgk PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5fgk RCSB], [http://www.ebi.ac.uk/pdbsum/5fgk PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5fgk ProSAT]</span></td></tr>
	</table>		</table>
	== Function ==		== Function ==
Line 18:		Line 19:
	</div>		</div>
	<div class="pdbe-citations 5fgk" style="background-color:#fffaf0;"></div>		<div class="pdbe-citations 5fgk" style="background-color:#fffaf0;"></div>
		+
		+	==See Also==
		+	*[[Cyclin 3D structures\|Cyclin 3D structures]]
		+	*[[Cyclin-dependent kinase 3D structures\|Cyclin-dependent kinase 3D structures]]
	== References ==		== References ==
	<references/>		<references/>
	__TOC__		__TOC__
	</StructureSection>		</StructureSection>
		+	[[Category: Human]]
		+	[[Category: Large Structures]]
	[[Category: Blagg, J]]		[[Category: Blagg, J]]
	[[Category: Mallinger, A]]		[[Category: Mallinger, A]]

OCA at 10:08, 26 February 2016

2016-02-26T10:08:01Z

←Older revision		Revision as of 10:08, 26 February 2016
Line 1:		Line 1:
		+
	==CDK8-CYCC IN COMPLEX WITH 8-[3-(3-Amino-1H-indazol-6-yl)-5-chloro- pyridine-4-yl]-2,8-diaza-spiro[4.5]decan-1-one==		==CDK8-CYCC IN COMPLEX WITH 8-[3-(3-Amino-1H-indazol-6-yl)-5-chloro- pyridine-4-yl]-2,8-diaza-spiro[4.5]decan-1-one==
	<StructureSection load='5fgk' size='340' side='right' caption='[[5fgk]], [[Resolution\|resolution]] 2.36Å' scene=''>		<StructureSection load='5fgk' size='340' side='right' caption='[[5fgk]], [[Resolution\|resolution]] 2.36Å' scene=''>

OCA at 15:31, 3 February 2016

2016-02-03T15:31:52Z

←Older revision		Revision as of 15:31, 3 February 2016
Line 1:		Line 1:
-	'''~~Unreleased~~ structure'''	+	==CDK8-CYCC IN COMPLEX WITH 8-[3-(3-Amino-1H-indazol-6-yl)-5-chloro- pyridine-4-yl]-2,8-diaza-spiro[4.5]decan-1-one==
		+	<StructureSection load='5fgk' size='340' side='right' caption='[[5fgk]], [[Resolution\|resolution]] 2.36Å' scene=''>
		+	== Structural highlights ==
		+	<table><tr><td colspan='2'>[[5fgk]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5FGK OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5FGK FirstGlance]. <br>
		+	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=5XG:8-[3-(3-AZANYL-2~{H}-INDAZOL-6-YL)-5-CHLORANYL-PYRIDIN-4-YL]-2,8-DIAZASPIRO[4.5]DECAN-1-ONE'>5XG</scene>, <scene name='pdbligand=DMS:DIMETHYL+SULFOXIDE'>DMS</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=FMT:FORMIC+ACID'>FMT</scene></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=5fgk FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5fgk OCA], [http://pdbe.org/5fgk PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5fgk RCSB], [http://www.ebi.ac.uk/pdbsum/5fgk PDBsum]</span></td></tr>
		+	</table>
		+	== Function ==
		+	[[http://www.uniprot.org/uniprot/CDK8_HUMAN CDK8_HUMAN]] Component of the Mediator complex, a coactivator involved in regulated gene transcription of nearly all RNA polymerase II-dependent genes. Mediator functions as a bridge to convey information from gene-specific regulatory proteins to the basal RNA polymerase II transcription machinery. Mediator is recruited to promoters by direct interactions with regulatory proteins and serves as a scaffold for the assembly of a functional preinitiation complex with RNA polymerase II and the general transcription factors. Phosphorylates the CTD (C-terminal domain) of the large subunit of RNA polymerase II (RNAp II), which may inhibit the formation of a transcription initiation complex. Phosphorylates CCNH leading to down-regulation of the TFIIH complex and transcriptional repression. Recruited through interaction with MAML1 to hyperphosphorylate the intracellular domain of NOTCH, leading to its degradation.<ref>PMID:10993082</ref> <ref>PMID:15546612</ref> [[http://www.uniprot.org/uniprot/CCNC_HUMAN CCNC_HUMAN]] Component of the Mediator complex, a coactivator involved in regulated gene transcription of nearly all RNA polymerase II-dependent genes. Mediator functions as a bridge to convey information from gene-specific regulatory proteins to the basal RNA polymerase II transcription machinery. Mediator is recruited to promoters by direct interactions with regulatory proteins and serves as a scaffold for the assembly of a functional preinitiation complex with RNA polymerase II and the general transcription factors. Binds to and activates cyclin-dependent kinase CDK8 that phosphorylates the CTD (C-terminal domain) of the large subunit of RNA polymerase II (RNAp II), which may inhibit the formation of a transcription initiation complex.<ref>PMID:8700522</ref> <ref>PMID:16595664</ref>
		+	<div style="background-color:#fffaf0;">
		+	== Publication Abstract from PubMed ==
		+	The Mediator complex-associated cyclin-dependent kinase CDK8 has been implicated in human disease, particularly in colorectal cancer where it has been reported as a putative oncogene. Here we report the discovery of 109 (CCT251921), a potent, selective, and orally bioavailable inhibitor of CDK8 with equipotent affinity for CDK19. We describe a structure-based design approach leading to the discovery of a 3,4,5-trisubstituted-2-aminopyridine series and present the application of physicochemical property analyses to successfully reduce in vivo metabolic clearance, minimize transporter-mediated biliary elimination while maintaining acceptable aqueous solubility. Compound 109 affords the optimal compromise of in vitro biochemical, pharmacokinetic, and physicochemical properties and is suitable for progression to animal models of cancer.

-	~~The entry 5fgk is ON HOLD~~	+	Discovery of Potent, Selective, and Orally Bioavailable Small-Molecule Modulators of the Mediator Complex-Associated Kinases CDK8 and CDK19.,Mallinger A, Schiemann K, Rink C, Stieber F, Calderini M, Crumpler S, Stubbs M, Adeniji-Popoola O, Poeschke O, Busch M, Czodrowski P, Musil D, Schwarz D, Ortiz-Ruiz MJ, Schneider R, Thai C, Valenti M, de Haven Brandon A, Burke R, Workman P, Dale T, Wienke D, Clarke PA, Esdar C, Raynaud FI, Eccles SA, Rohdich F, Blagg J J Med Chem. 2016 Jan 21. PMID:26796641<ref>PMID:26796641</ref>

-	~~Authors: Musil~~, D.~~, Blagg, J~~.~~, Mallinger, A~~.	+	From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
-		+	</div>
-	~~Description: CDK8~~-~~CYCC IN COMPLEX WITH 8~~-~~[3-(3-Amino-1H-indazol-6-yl)-5-chloro-pyridine-4-yl]-2,8-diaza-spiro[4.5]decan-1-one~~	+	<div class="pdbe-citations 5fgk" style="background-color:#fffaf0;"></div>
-	~~[[Category~~: ~~Unreleased Structures]]~~	+	== References ==
-	~~[[Category: Musil, D]]~~	+	<references/>
		+	__TOC__
		+	</StructureSection>
	[[Category: Blagg, J]]		[[Category: Blagg, J]]
	[[Category: Mallinger, A]]		[[Category: Mallinger, A]]
		+	[[Category: Musil, D]]
		+	[[Category: Cdk8 kinase / cyclin c]]
		+	[[Category: Transferase]]

OCA at 14:36, 20 January 2016

2016-01-20T14:36:22Z

←Older revision		Revision as of 14:36, 20 January 2016
Line 3:		Line 3:
	The entry 5fgk is ON HOLD		The entry 5fgk is ON HOLD

-	Authors: ~~MUSIL~~, D., ~~BLAGG~~, J., ~~MALLINGER~~, A.	+	Authors: Musil, D., Blagg, J., Mallinger, A.

	Description: CDK8-CYCC IN COMPLEX WITH 8-[3-(3-Amino-1H-indazol-6-yl)-5-chloro-pyridine-4-yl]-2,8-diaza-spiro[4.5]decan-1-one		Description: CDK8-CYCC IN COMPLEX WITH 8-[3-(3-Amino-1H-indazol-6-yl)-5-chloro-pyridine-4-yl]-2,8-diaza-spiro[4.5]decan-1-one

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

2015-12-30T17:55:01Z

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

←Older revision

Revision as of 17:55, 30 December 2015

OCA: New page: '''Unreleased structure''' The entry 5fgk is ON HOLD Authors: MUSIL, D., BLAGG, J., MALLINGER, A. Description: CDK8-CYCC IN COMPLEX WITH 8-[3-(3-Amino-1H-indazol-6-yl)-5-chloro-pyridin...

2015-12-30T17:55:00Z

New page: '''Unreleased structure''' The entry 5fgk is ON HOLD Authors: MUSIL, D., BLAGG, J., MALLINGER, A. Description: CDK8-CYCC IN COMPLEX WITH 8-[3-(3-Amino-1H-indazol-6-yl)-5-chloro-pyridin...

New page

'''Unreleased structure'''

The entry 5fgk is ON HOLD

Authors: MUSIL, D., BLAGG, J., MALLINGER, A.

Description: CDK8-CYCC IN COMPLEX WITH 8-[3-(3-Amino-1H-indazol-6-yl)-5-chloro-pyridine-4-yl]-2,8-diaza-spiro[4.5]decan-1-one
[[Category: Unreleased Structures]]
[[Category: Musil, D]]
[[Category: Blagg, J]]
[[Category: Mallinger, A]]