4crl

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'''Unreleased structure'''
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==Crystal structure of human CDK8-Cyclin C in complex with cortistatin A==
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<StructureSection load='4crl' size='340' side='right' caption='[[4crl]], [[Resolution|resolution]] 2.40&Aring;' scene=''>
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== Structural highlights ==
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<table><tr><td colspan='2'>[[4crl]] is a 2 chain structure. 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>
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</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>
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<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>
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<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]</span></td></tr>
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</table>
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== Function ==
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[[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>
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<div style="background-color:#fffaf0;">
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== Publication Abstract from PubMed ==
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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.
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The entry 4crl is ON HOLD until Paper Publication
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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<ref>PMID:26416749</ref>
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Authors: Pelish, H.E., Liau, B.B., Tangpeerachaikul, A., Poss, Z.C., DaSilva, D.H., Caruso, B.T., Arefolov, A., Fadeyi, O., Christie, A.L., Du, K., Banka, D., Schneider, E.V., Jestel, A., Wilson, C.J., Mapa, F.A., Flyer, A.N., Nordin, B.E., Zou, G., Si, C., Bronson, R.T., Patricelli, M.P., Krivtsov, A., Myers, A.G., Kohl, N.E., Kung, A.L., Armstrong, S.A., Lemieux, M.E., Taatjes, D.J., Shair, M.D.
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From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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</div>
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Description: Specific inhibition of Mediator kinases as a therapeutic approach for acute myeloid leukaemia
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<div class="pdbe-citations 4crl" style="background-color:#fffaf0;"></div>
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[[Category: Unreleased Structures]]
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== References ==
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[[Category: Si, C]]
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<references/>
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[[Category: Banka, D]]
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__TOC__
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[[Category: Arefolov, A]]
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</StructureSection>
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[[Category: Tangpeerachaikul, A]]
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[[Category: Cyclin-dependent kinase]]
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[[Category: Poss, Z.C]]
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[[Category: Myers, A G]]
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[[Category: Shair, M.D]]
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[[Category: Shair, M D]]
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[[Category: Liau, B.B]]
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[[Category: Ccnc]]
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[[Category: Mapa, F.A]]
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[[Category: Cdk8]]
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[[Category: Caruso, B.T]]
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[[Category: Cortistatin some]]
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[[Category: Pelish, H.E]]
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[[Category: Cyclin c]]
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[[Category: Nordin, B.E]]
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[[Category: Cyclin-dependent kinase 8]]
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[[Category: Flyer, A.N]]
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[[Category: Mediator complex]]
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[[Category: Wilson, C.J]]
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[[Category: Mediator kinase]]
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[[Category: Schneider, E.V]]
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[[Category: Super-enhancer]]
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[[Category: Lemieux, M.E]]
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[[Category: Transcription]]
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[[Category: Krivtsov, A]]
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[[Category: Transferase]]
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[[Category: Kung, A.L]]
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[[Category: Zou, G]]
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[[Category: Kohl, N.E]]
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[[Category: Armstrong, S.A]]
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[[Category: Patricelli, M.P]]
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[[Category: Jestel, A]]
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[[Category: Fadeyi, O]]
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[[Category: Taatjes, D.J]]
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[[Category: Du, K]]
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[[Category: Dasilva, D.H]]
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[[Category: Christie, A.L]]
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[[Category: Myers, A.G]]
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[[Category: Bronson, R.T]]
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Revision as of 07:31, 7 October 2015

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

4crl, resolution 2.40Å

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