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| | <StructureSection load='6t41' size='340' side='right'caption='[[6t41]], [[Resolution|resolution]] 2.45Å' scene=''> | | <StructureSection load='6t41' size='340' side='right'caption='[[6t41]], [[Resolution|resolution]] 2.45Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[6t41]] 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=6T41 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6T41 FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[6t41]] 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=6T41 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6T41 FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=FMT:FORMIC+ACID'>FMT</scene>, <scene name='pdbligand=MFE:~{N}-[(4-chlorophenyl)methyl]quinazolin-4-amine'>MFE</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]] 2.45Å</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=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=FMT:FORMIC+ACID'>FMT</scene>, <scene name='pdbligand=MFE:~{N}-[(4-chlorophenyl)methyl]quinazolin-4-amine'>MFE</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=6t41 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6t41 OCA], [http://pdbe.org/6t41 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6t41 RCSB], [http://www.ebi.ac.uk/pdbsum/6t41 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6t41 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=6t41 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6t41 OCA], [https://pdbe.org/6t41 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6t41 RCSB], [https://www.ebi.ac.uk/pdbsum/6t41 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6t41 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/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;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
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| | </div> | | </div> |
| | <div class="pdbe-citations 6t41" style="background-color:#fffaf0;"></div> | | <div class="pdbe-citations 6t41" 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: Homo sapiens]] |
| | [[Category: Large Structures]] | | [[Category: Large Structures]] |
| - | [[Category: Huber, R]] | + | [[Category: Huber R]] |
| - | [[Category: Kuhn, C D]] | + | [[Category: Kuhn C-D]] |
| - | [[Category: Maskos, K]] | + | [[Category: Maskos K]] |
| - | [[Category: Schneider, E V]] | + | [[Category: Schneider EV]] |
| - | [[Category: Cyclin-dependent kinase]]
| + | |
| - | [[Category: Inhibitor complex]]
| + | |
| - | [[Category: Mediator]]
| + | |
| - | [[Category: Mediator kinase module]]
| + | |
| - | [[Category: Transcription]]
| + | |
| - | [[Category: Transcriptional kinase]]
| + | |
| Structural highlights
Function
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.[1] [2]
Publication Abstract from PubMed
The Mediator kinase module regulates eukaryotic transcription by phosphorylating transcription-related targets and by modulating the association of Mediator and RNA polymerase II. The activity of its catalytic core, cyclin-dependent kinase 8 (CDK8), is controlled by Cyclin C and regulatory subunit MED12, with its deregulation contributing to numerous malignancies. Here, we combine in vitro biochemistry, cross-linking coupled to mass spectrometry, and in vivo studies to describe the binding location of the N-terminal segment of MED12 on the CDK8/Cyclin C complex and to gain mechanistic insights into the activation of CDK8 by MED12. Our data demonstrate that the N-terminal portion of MED12 wraps around CDK8, whereby it positions an "activation helix" close to the T-loop of CDK8 for its activation. Intriguingly, mutations in the activation helix that are frequently found in cancers do not diminish the affinity of MED12 for CDK8, yet likely alter the exact positioning of the activation helix. Furthermore, we find the transcriptome-wide gene-expression changes in human cells that result from a mutation in the MED12 activation helix to correlate with deregulated genes in breast and colon cancer. Finally, functional assays in the presence of kinase inhibitors reveal that binding of MED12 remodels the active site of CDK8 and thereby precludes the inhibition of ternary CDK8 complexes by type II kinase inhibitors. Taken together, our results not only allow us to propose a revised model of how CDK8 activity is regulated by MED12, but also offer a path forward in developing small molecules that target CDK8 in its MED12-bound form.
A precisely positioned MED12 activation helix stimulates CDK8 kinase activity.,Klatt F, Leitner A, Kim IV, Ho-Xuan H, Schneider EV, Langhammer F, Weinmann R, Muller MR, Huber R, Meister G, Kuhn CD Proc Natl Acad Sci U S A. 2020 Feb 11;117(6):2894-2905. doi:, 10.1073/pnas.1917635117. Epub 2020 Jan 27. PMID:31988137[3]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ 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
- ↑ Klatt F, Leitner A, Kim IV, Ho-Xuan H, Schneider EV, Langhammer F, Weinmann R, Muller MR, Huber R, Meister G, Kuhn CD. A precisely positioned MED12 activation helix stimulates CDK8 kinase activity. Proc Natl Acad Sci U S A. 2020 Feb 11;117(6):2894-2905. doi:, 10.1073/pnas.1917635117. Epub 2020 Jan 27. PMID:31988137 doi:http://dx.doi.org/10.1073/pnas.1917635117
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