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5bnj

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CDK8/CYCC IN COMPLEX WITH 8-{3-Chloro-5-[4-(1-methyl-1H-pyrazol-4-yl)-phenyl]-pyridin- 4-yl}-2,8-diaza-spiro[4.5]decan-1-one

Structural highlights

5bnj is a 2 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 2.64Å
Ligands:	,
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

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.^[1] ^[2]

Publication Abstract from PubMed

There is unmet need for chemical tools to explore the role of the Mediator complex in human pathologies ranging from cancer to cardiovascular disease. Here we determine that CCT251545, a small-molecule inhibitor of the WNT pathway discovered through cell-based screening, is a potent and selective chemical probe for the human Mediator complex-associated protein kinases CDK8 and CDK19 with >100-fold selectivity over 291 other kinases. X-ray crystallography demonstrates a type 1 binding mode involving insertion of the CDK8 C terminus into the ligand binding site. In contrast to type II inhibitors of CDK8 and CDK19, CCT251545 displays potent cell-based activity. We show that CCT251545 and close analogs alter WNT pathway-regulated gene expression and other on-target effects of modulating CDK8 and CDK19, including expression of genes regulated by STAT1. Consistent with this, we find that phosphorylation of STAT1(SER727) is a biomarker of CDK8 kinase activity in vitro and in vivo. Finally, we demonstrate in vivo activity of CCT251545 in WNT-dependent tumors.

A selective chemical probe for exploring the role of CDK8 and CDK19 in human disease.,Dale T, Clarke PA, Esdar C, Waalboer D, Adeniji-Popoola O, Ortiz-Ruiz MJ, Mallinger A, Samant RS, Czodrowski P, Musil D, Schwarz D, Schneider K, Stubbs M, Ewan K, Fraser E, TePoele R, Court W, Box G, Valenti M, de Haven Brandon A, Gowan S, Rohdich F, Raynaud F, Schneider R, Poeschke O, Blaukat A, Workman P, Schiemann K, Eccles SA, Wienke D, Blagg J Nat Chem Biol. 2015 Dec;11(12):973-80. doi: 10.1038/nchembio.1952. Epub 2015 Oct , 26. PMID:26502155^[3]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Akoulitchev S, Chuikov S, Reinberg D. TFIIH is negatively regulated by cdk8-containing mediator complexes. Nature. 2000 Sep 7;407(6800):102-6. PMID:10993082 doi:10.1038/35024111
↑ Fryer CJ, White JB, Jones KA. Mastermind recruits CycC:CDK8 to phosphorylate the Notch ICD and coordinate activation with turnover. Mol Cell. 2004 Nov 19;16(4):509-20. PMID:15546612 doi:S1097276504006409
↑ Dale T, Clarke PA, Esdar C, Waalboer D, Adeniji-Popoola O, Ortiz-Ruiz MJ, Mallinger A, Samant RS, Czodrowski P, Musil D, Schwarz D, Schneider K, Stubbs M, Ewan K, Fraser E, TePoele R, Court W, Box G, Valenti M, de Haven Brandon A, Gowan S, Rohdich F, Raynaud F, Schneider R, Poeschke O, Blaukat A, Workman P, Schiemann K, Eccles SA, Wienke D, Blagg J. A selective chemical probe for exploring the role of CDK8 and CDK19 in human disease. Nat Chem Biol. 2015 Dec;11(12):973-80. doi: 10.1038/nchembio.1952. Epub 2015 Oct , 26. PMID:26502155 doi:http://dx.doi.org/10.1038/nchembio.1952

1 Structural highlights
2 Function
3 Publication Abstract from PubMed
4 See Also
5 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/5bnj"

Categories: Homo sapiens | Large Structures | Blagg J | Musil D | Wienke D

@@ Line 4: / Line 4: @@
 == Structural highlights ==
 <table><tr><td colspan='2'>[[5bnj]] 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=5BNJ OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5BNJ FirstGlance]. <br>
-</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=4TV:8-{3-CHLORO-5-[4-(1-METHYL-1H-PYRAZOL-4-YL)PHENYL]PYRIDIN-4-YL}-2,8-DIAZASPIRO[4.5]DECAN-1-ONE'>4TV</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]] 2.64&#8491;</td></tr>
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=4TV:8-{3-CHLORO-5-[4-(1-METHYL-1H-PYRAZOL-4-YL)PHENYL]PYRIDIN-4-YL}-2,8-DIAZASPIRO[4.5]DECAN-1-ONE'>4TV</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'>[https://proteopedia.org/fgij/fg.htm?mol=5bnj FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5bnj OCA], [https://pdbe.org/5bnj PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5bnj RCSB], [https://www.ebi.ac.uk/pdbsum/5bnj PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5bnj ProSAT]</span></td></tr>
 </table>

5bnj

From Proteopedia

Current revision

CDK8/CYCC IN COMPLEX WITH 8-{3-Chloro-5-[4-(1-methyl-1H-pyrazol-4-yl)-phenyl]-pyridin- 4-yl}-2,8-diaza-spiro[4.5]decan-1-one

Structural highlights

Function

Publication Abstract from PubMed

See Also

References

Contents

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