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| | ==CDK8/CYCC IN COMPLEX WITH COMPOUND 20== | | ==CDK8/CYCC IN COMPLEX WITH COMPOUND 20== |
| - | <StructureSection load='5hvy' size='340' side='right' caption='[[5hvy]], [[Resolution|resolution]] 2.39Å' scene=''> | + | <StructureSection load='5hvy' size='340' side='right'caption='[[5hvy]], [[Resolution|resolution]] 2.39Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[5hvy]] 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=5HVY OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5HVY FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[5hvy]] 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=5HVY OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5HVY FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=66X:N-{(3S)-1-[2-(METHYLAMINO)PYRIMIDIN-4-YL]PYRROLIDIN-3-YL}-N-{4-[(MORPHOLIN-4-YL)METHYL]-3-(TRIFLUOROMETHYL)PHENYL}UREA'>66X</scene>, <scene name='pdbligand=CL:CHLORIDE+ION'>CL</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]] 2.39Å</td></tr> |
| - | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[5cei|5cei]]</td></tr>
| + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=66X:N-{(3S)-1-[2-(METHYLAMINO)PYRIMIDIN-4-YL]PYRROLIDIN-3-YL}-N-{4-[(MORPHOLIN-4-YL)METHYL]-3-(TRIFLUOROMETHYL)PHENYL}UREA'>66X</scene>, <scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=FMT:FORMIC+ACID'>FMT</scene></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'>[https://proteopedia.org/fgij/fg.htm?mol=5hvy FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5hvy OCA], [https://pdbe.org/5hvy PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5hvy RCSB], [https://www.ebi.ac.uk/pdbsum/5hvy PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5hvy ProSAT]</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=5hvy FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5hvy OCA], [http://pdbe.org/5hvy PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5hvy RCSB], [http://www.ebi.ac.uk/pdbsum/5hvy PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5hvy 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 == |
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| | </div> | | </div> |
| | <div class="pdbe-citations 5hvy" style="background-color:#fffaf0;"></div> | | <div class="pdbe-citations 5hvy" 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: Bergeron, P]] | + | [[Category: Large Structures]] |
| - | [[Category: Kiefer, J R]] | + | [[Category: Bergeron P]] |
| - | [[Category: Koehler, M]] | + | [[Category: Kiefer JR]] |
| - | [[Category: Maskos, K]] | + | [[Category: Koehler M]] |
| - | [[Category: Schneider, E V]] | + | [[Category: Maskos K]] |
| - | [[Category: Transferase-transcription complex]]
| + | [[Category: Schneider EV]] |
| Structural highlights
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
Using Sorafenib as a starting point, a series of potent and selective inhibitors of CDK8 was developed. When cocrystallized with CDK8 and cyclin C, these compounds exhibit a Type-II (DMG-out) binding mode.
Design and Development of a Series of Potent and Selective Type II Inhibitors of CDK8.,Bergeron P, Koehler MF, Blackwood EM, Bowman K, Clark K, Firestein R, Kiefer JR, Maskos K, McCleland ML, Orren L, Ramaswamy S, Salphati L, Schmidt S, Schneider EV, Wu J, Beresini M ACS Med Chem Lett. 2016 Apr 5;7(6):595-600. doi: 10.1021/acsmedchemlett.6b00044. , eCollection 2016 Jun 9. PMID:27326333[3]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
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
- ↑ Bergeron P, Koehler MF, Blackwood EM, Bowman K, Clark K, Firestein R, Kiefer JR, Maskos K, McCleland ML, Orren L, Ramaswamy S, Salphati L, Schmidt S, Schneider EV, Wu J, Beresini M. Design and Development of a Series of Potent and Selective Type II Inhibitors of CDK8. ACS Med Chem Lett. 2016 Apr 5;7(6):595-600. doi: 10.1021/acsmedchemlett.6b00044. , eCollection 2016 Jun 9. PMID:27326333 doi:http://dx.doi.org/10.1021/acsmedchemlett.6b00044
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