5idn - Revision history

OCA at 13:47, 30 August 2023

OCA — Wed, 30 Aug 2023 13:47:04 GMT

←Older revision		Revision as of 13:47, 30 August 2023
Line 3:		Line 3:
	<StructureSection load='5idn' size='340' side='right'caption='[[5idn]], [[Resolution\|resolution]] 2.26Å' scene=''>		<StructureSection load='5idn' size='340' side='right'caption='[[5idn]], [[Resolution\|resolution]] 2.26Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
-	<table><tr><td colspan='2'>[[5idn]] 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=5IDN OCA]. For a <b>guided tour on the structure components</b> use [~~http~~://proteopedia.org/fgij/fg.htm?mol=5IDN FirstGlance]. <br>	+	<table><tr><td colspan='2'>[[5idn]] 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=5IDN OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5IDN FirstGlance]. <br>
-	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=6A7:[(2S)-2-(4-CHLOROPHENYL)PYRROLIDIN-1-YL](3-METHYL-1H-PYRAZOLO[3,4-B]PYRIDIN-5-YL)METHANONE'>6A7</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]] 2.26Å</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=6A7:[(2S)-2-(4-CHLOROPHENYL)PYRROLIDIN-1-YL](3-METHYL-1H-PYRAZOLO[3,4-B]PYRIDIN-5-YL)METHANONE'>6A7</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=5idn FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5idn OCA], [~~http~~://pdbe.org/5idn PDBe], [~~http~~://www.rcsb.org/pdb/explore.do?structureId=5idn RCSB], [~~http~~://www.ebi.ac.uk/pdbsum/5idn PDBsum], [~~http~~://prosat.h-its.org/prosat/prosatexe?pdbcode=5idn 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=5idn FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5idn OCA], [https://pdbe.org/5idn PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5idn RCSB], [https://www.ebi.ac.uk/pdbsum/5idn PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5idn 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 ==
Line 27:		Line 27:
	__TOC__		__TOC__
	</StructureSection>		</StructureSection>
-	[[Category: ~~Human~~]]	+	[[Category: Homo sapiens]]
	[[Category: Large Structures]]		[[Category: Large Structures]]
-	[[Category: Blagg, J]]	+	[[Category: Blagg J]]
-	[[Category: Czodrowski, P]]	+	[[Category: Czodrowski P]]
-	[[Category: Mallinger, A]]	+	[[Category: Mallinger A]]
-	[[Category: Musil, D]]	+	[[Category: Musil D]]
-	[[Category: Schiemann, K]]	+	[[Category: Schiemann K]]
-	~~[[Category: Cdk8 kinase / cyclin c]]~~	+
-	~~[[Category: Transferase~~]]	+

OCA at 07:14, 3 June 2020

OCA — Wed, 03 Jun 2020 07:14:14 GMT

←Older revision		Revision as of 07:14, 3 June 2020
Line 1:		Line 1:

	==CDK8-CYCC IN COMPLEX WITH [(S)-2-(4-Chloro-phenyl)-pyrrolidin-1-yl]-(3-methyl-1H-pyrazolo[3,4-b]pyridin-5-yl)-methanone==		==CDK8-CYCC IN COMPLEX WITH [(S)-2-(4-Chloro-phenyl)-pyrrolidin-1-yl]-(3-methyl-1H-pyrazolo[3,4-b]pyridin-5-yl)-methanone==
-	<StructureSection load='5idn' size='340' side='right' caption='[[5idn]], [[Resolution\|resolution]] 2.26Å' scene=''>	+	<StructureSection load='5idn' size='340' side='right'caption='[[5idn]], [[Resolution\|resolution]] 2.26Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
-	<table><tr><td colspan='2'>[[5idn]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5IDN OCA]. For a <b>guided tour on the structure components</b> use [http://~~oca~~.~~weizmann.ac.il/oca-docs~~/fgij/fg.htm?mol=5IDN FirstGlance]. <br>	+	<table><tr><td colspan='2'>[[5idn]] 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=5IDN OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=5IDN FirstGlance]. <br>
-	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=6A7:[(2S)-2-(4-CHLOROPHENYL)PYRROLIDIN-1-YL](3-METHYL-1H-PYRAZOLO[3,4-B]PYRIDIN-5-YL)METHANONE'>6A7</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=6A7:[(2S)-2-(4-CHLOROPHENYL)PYRROLIDIN-1-YL](3-METHYL-1H-PYRAZOLO[3,4-B]PYRIDIN-5-YL)METHANONE'>6A7</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=5idn FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5idn OCA], [http://pdbe.org/5idn PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5idn RCSB], [http://www.ebi.ac.uk/pdbsum/5idn PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5idn ProSAT]</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=5idn FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5idn OCA], [http://pdbe.org/5idn PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5idn RCSB], [http://www.ebi.ac.uk/pdbsum/5idn PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5idn ProSAT]</span></td></tr>
	</table>		</table>
	== Function ==		== Function ==
Line 18:		Line 19:
	</div>		</div>
	<div class="pdbe-citations 5idn" style="background-color:#fffaf0;"></div>		<div class="pdbe-citations 5idn" 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: Czodrowski, P]]		[[Category: Czodrowski, P]]

OCA at 21:24, 22 December 2016

OCA — Thu, 22 Dec 2016 21:24:54 GMT

←Older revision		Revision as of 21:24, 22 December 2016
Line 1:		Line 1:
-	'''Unreleased structure'''

-	~~The entry~~ 5idn is ~~ON HOLD~~ ~~until Paper~~ Publication	+	==CDK8-CYCC IN COMPLEX WITH [(S)-2-(4-Chloro-phenyl)-pyrrolidin-1-yl]-(3-methyl-1H-pyrazolo[3,4-b]pyridin-5-yl)-methanone==
		+	<StructureSection load='5idn' size='340' side='right' caption='[[5idn]], [[Resolution\|resolution]] 2.26Å' scene=''>
		+	== Structural highlights ==
		+	<table><tr><td colspan='2'>[[5idn]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5IDN OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5IDN FirstGlance]. <br>
		+	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=6A7:[(2S)-2-(4-CHLOROPHENYL)PYRROLIDIN-1-YL](3-METHYL-1H-PYRAZOLO[3,4-B]PYRIDIN-5-YL)METHANONE'>6A7</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=5idn FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5idn OCA], [http://pdbe.org/5idn PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5idn RCSB], [http://www.ebi.ac.uk/pdbsum/5idn PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5idn ProSAT]</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 regulates beta-catenin-dependent transcription following activation of WNT signaling. Multiple lines of evidence suggest CDK8 may act as an oncogene in the development of colorectal cancer. Here we describe the successful optimization of an imidazo-thiadiazole series of CDK8 inhibitors that was identified in a high-throughput screening campaign and further progressed by structure-based design. In several optimization cycles, we improved the microsomal stability, potency, and kinase selectivity. The initial imidazo-thiadiazole scaffold was replaced by a 3-methyl-1H-pyrazolo[3,4-b]-pyridine which resulted in compound 25 (MSC2530818) that displayed excellent kinase selectivity, biochemical and cellular potency, microsomal stability, and is orally bioavailable. Furthermore, we demonstrated modulation of phospho-STAT1, a pharmacodynamic biomarker of CDK8 activity, and tumor growth inhibition in an APC mutant SW620 human colorectal carcinoma xenograft model after oral administration. Compound 25 demonstrated suitable potency and selectivity to progress into preclinical in vivo efficacy and safety studies.

-	~~Authors: Musil~~, D., ~~Blagg, J~~., ~~Mallinger~~, A., ~~Czodrowski~~, P., ~~Schiemann~~, K.	+	Structure-Based Optimization of Potent, Selective, and Orally Bioavailable CDK8 Inhibitors Discovered by High-Throughput Screening.,Czodrowski P, Mallinger A, Wienke D, Esdar C, Poschke O, Busch M, Rohdich F, Eccles SA, Ortiz-Ruiz MJ, Schneider R, Raynaud FI, Clarke PA, Musil D, Schwarz D, Dale T, Urbahns K, Blagg J, Schiemann K J Med Chem. 2016 Oct 27;59(20):9337-9349. Epub 2016 Oct 7. PMID:27490956<ref>PMID:27490956</ref>

-	~~Description: CDK8-CYCC IN COMPLEX WITH [(~~S)-2-~~(4-Chloro-phenyl)-pyrrolidin-1-yl]-(3-methyl-1H-pyrazolo[3,4-b]pyridin-5-yl)-methanone~~	+	From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
-	~~[[Category~~: ~~Unreleased Structures]]~~	+	</div>
-	~~[[Category: Musil, D]]~~	+	<div class="pdbe-citations 5idn" style="background-color:#fffaf0;"></div>
		+	== References ==
		+	<references/>
		+	__TOC__
		+	</StructureSection>
	[[Category: Blagg, J]]		[[Category: Blagg, J]]
	[[Category: Czodrowski, P]]		[[Category: Czodrowski, P]]
-	[[Category: Schiemann, K]]
	[[Category: Mallinger, A]]		[[Category: Mallinger, A]]
		+	[[Category: Musil, D]]
		+	[[Category: Schiemann, K]]
		+	[[Category: Cdk8 kinase / cyclin c]]
		+	[[Category: Transferase]]

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

OCA — Wed, 02 Mar 2016 13:48:04 GMT

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

←Older revision

Revision as of 13:48, 2 March 2016

OCA: New page: '''Unreleased structure''' The entry 5idn is ON HOLD until Paper Publication Authors: Musil, D., Blagg, J., Mallinger, A., Czodrowski, P., Schiemann, K. Description: CDK8-CYCC IN COMPL...

OCA — Wed, 02 Mar 2016 13:48:03 GMT

New page: '''Unreleased structure''' The entry 5idn is ON HOLD until Paper Publication Authors: Musil, D., Blagg, J., Mallinger, A., Czodrowski, P., Schiemann, K. Description: CDK8-CYCC IN COMPL...

New page

'''Unreleased structure'''

The entry 5idn is ON HOLD until Paper Publication

Authors: Musil, D., Blagg, J., Mallinger, A., Czodrowski, P., Schiemann, K.

Description: CDK8-CYCC IN COMPLEX WITH [(S)-2-(4-Chloro-phenyl)-pyrrolidin-1-yl]-(3-methyl-1H-pyrazolo[3,4-b]pyridin-5-yl)-methanone
[[Category: Unreleased Structures]]
[[Category: Musil, D]]
[[Category: Blagg, J]]
[[Category: Czodrowski, P]]
[[Category: Schiemann, K]]
[[Category: Mallinger, A]]