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4crl

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Revision as of 08:18, 4 November 2020

Crystal structure of human CDK8-Cyclin C in complex with cortistatin A

Structural highlights

4crl is a 2 chain structure with sequence from Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:	,
Activity:	Cyclin-dependent kinase, with EC number 2.7.11.22
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] [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.^[3] ^[4]

Publication Abstract from PubMed

Super-enhancers (SEs), which are composed of large clusters of enhancers densely loaded with the Mediator complex, transcription factors and chromatin regulators, drive high expression of genes implicated in cell identity and disease, such as lineage-controlling transcription factors and oncogenes. BRD4 and CDK7 are positive regulators of SE-mediated transcription. By contrast, negative regulators of SE-associated genes have not been well described. Here we show that the Mediator-associated kinases cyclin-dependent kinase 8 (CDK8) and CDK19 restrain increased activation of key SE-associated genes in acute myeloid leukaemia (AML) cells. We report that the natural product cortistatin A (CA) selectively inhibits Mediator kinases, has anti-leukaemic activity in vitro and in vivo, and disproportionately induces upregulation of SE-associated genes in CA-sensitive AML cell lines but not in CA-insensitive cell lines. In AML cells, CA upregulated SE-associated genes with tumour suppressor and lineage-controlling functions, including the transcription factors CEBPA, IRF8, IRF1 and ETV6 (refs 6, 7, 8). The BRD4 inhibitor I-BET151 downregulated these SE-associated genes, yet also has anti-leukaemic activity. Individually increasing or decreasing the expression of these transcription factors suppressed AML cell growth, providing evidence that leukaemia cells are sensitive to the dosage of SE-associated genes. Our results demonstrate that Mediator kinases can negatively regulate SE-associated gene expression in specific cell types, and can be pharmacologically targeted as a therapeutic approach to AML.

Mediator kinase inhibition further activates super-enhancer-associated genes in AML.,Pelish HE, Liau BB, Nitulescu II, Tangpeerachaikul A, Poss ZC, Da Silva DH, Caruso BT, Arefolov A, Fadeyi O, Christie AL, Du K, Banka D, Schneider EV, Jestel A, Zou G, Si C, Ebmeier CC, Bronson RT, Krivtsov AV, Myers AG, Kohl NE, Kung AL, Armstrong SA, Lemieux ME, Taatjes DJ, Shair MD Nature. 2015 Sep 28. doi: 10.1038/nature14904. PMID:26416749^[5]

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
↑ Rickert P, Seghezzi W, Shanahan F, Cho H, Lees E. Cyclin C/CDK8 is a novel CTD kinase associated with RNA polymerase II. Oncogene. 1996 Jun 20;12(12):2631-40. PMID:8700522
↑ Baek HJ, Kang YK, Roeder RG. Human Mediator enhances basal transcription by facilitating recruitment of transcription factor IIB during preinitiation complex assembly. J Biol Chem. 2006 Jun 2;281(22):15172-81. Epub 2006 Apr 4. PMID:16595664 doi:M601983200
↑ Pelish HE, Liau BB, Nitulescu II, Tangpeerachaikul A, Poss ZC, Da Silva DH, Caruso BT, Arefolov A, Fadeyi O, Christie AL, Du K, Banka D, Schneider EV, Jestel A, Zou G, Si C, Ebmeier CC, Bronson RT, Krivtsov AV, Myers AG, Kohl NE, Kung AL, Armstrong SA, Lemieux ME, Taatjes DJ, Shair MD. Mediator kinase inhibition further activates super-enhancer-associated genes in AML. Nature. 2015 Sep 28. doi: 10.1038/nature14904. PMID:26416749 doi:http://dx.doi.org/10.1038/nature14904

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/4crl"

@@ Line 1: / Line 1: @@
 ==Crystal structure of human CDK8-Cyclin C in complex with cortistatin A==
-<StructureSection load='4crl' size='340' side='right' caption='[[4crl]], [[Resolution|resolution]] 2.40&Aring;' scene=''>
+<StructureSection load='4crl' size='340' side='right'caption='[[4crl]], [[Resolution|resolution]] 2.40&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[4crl]] 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=4CRL OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4CRL FirstGlance]. <br>
+<table><tr><td colspan='2'>[[4crl]] 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=4CRL OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=4CRL FirstGlance]. <br>
-</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=C1I:CORTISTATIN+A'>C1I</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=C1I:CORTISTATIN+A'>C1I</scene>, <scene name='pdbligand=FMT:FORMIC+ACID'>FMT</scene></td></tr>
 <tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Cyclin-dependent_kinase Cyclin-dependent kinase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.11.22 2.7.11.22] </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=4crl FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4crl OCA], [http://pdbe.org/4crl PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4crl RCSB], [http://www.ebi.ac.uk/pdbsum/4crl PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4crl 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=4crl FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4crl OCA], [http://pdbe.org/4crl PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4crl RCSB], [http://www.ebi.ac.uk/pdbsum/4crl PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4crl ProSAT]</span></td></tr>
 </table>
 == Function ==
@@ Line 19: / Line 19: @@
 </div>
 <div class="pdbe-citations 4crl" style="background-color:#fffaf0;"></div>
+==See Also==
+*[[Cyclin-dependent kinase 3D structures|Cyclin-dependent kinase 3D structures]]
 == References ==
 <references/>
@@ Line 25: / Line 28: @@
 [[Category: Cyclin-dependent kinase]]
 [[Category: Human]]
+[[Category: Large Structures]]
 [[Category: Myers, A G]]
 [[Category: Shair, M D]]

4crl

From Proteopedia

Revision as of 08:18, 4 November 2020

Crystal structure of human CDK8-Cyclin C in complex with cortistatin A

Structural highlights

Function

Publication Abstract from PubMed

See Also

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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