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==Crystal structure of CDK8:Cyclin C complex with compound 22==
==Crystal structure of CDK8:Cyclin C complex with compound 22==
<StructureSection load='5cei' size='340' side='right' caption='[[5cei]], [[Resolution|resolution]] 2.24&Aring;' scene=''>
<StructureSection load='5cei' size='340' side='right'caption='[[5cei]], [[Resolution|resolution]] 2.24&Aring;' scene=''>
== Structural highlights ==
== Structural highlights ==
<table><tr><td colspan='2'>[[5cei]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5CEI OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5CEI FirstGlance]. <br>
<table><tr><td colspan='2'>[[5cei]] 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=5CEI OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5CEI FirstGlance]. <br>
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=50R:4-(4-IODOPHENOXY)-N-METHYLTHIENO[2,3-C]PYRIDINE-2-CARBOXAMIDE'>50R</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</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]] 2.24&#8491;</td></tr>
<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[4g6l|4g6l]]</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=50R:4-(4-IODOPHENOXY)-N-METHYLTHIENO[2,3-C]PYRIDINE-2-CARBOXAMIDE'>50R</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</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'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5cei FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5cei OCA], [http://pdbe.org/5cei PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5cei RCSB], [http://www.ebi.ac.uk/pdbsum/5cei PDBsum]</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=5cei FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5cei OCA], [https://pdbe.org/5cei PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5cei RCSB], [https://www.ebi.ac.uk/pdbsum/5cei PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5cei 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;">
== Publication Abstract from PubMed ==
Beginning with promiscuous COT inhibitors, which were found to inhibit CDK8, a series of 6-aza-benzothiophene containing compounds were developed into potent, selective CDK8 inhibitors. When cocrystallized with CDK8 and cyclin C, these compounds exhibit an unusual binding mode, making a single hydrogen bond to the hinge residue A100, a second to K252, and a key cation-pi interaction with R356. Structure-based drug design resulted in tool compounds 13 and 32, which are highly potent, kinase selective, permeable compounds with a free fraction &gt;2% and no measurable efflux. Despite these attractive properties, these compounds exhibit weak antiproliferative activity in the HCT-116 colon cancer cell line. Further examination of the activity of 32 in this cell line revealed that the compound reduced phosphorylation of the known CDK8 substrate STAT1 in a manner identical to a CDK8 knockout clone, illustrating the complex effects of inhibition of CDK8 kinase activity in proliferation in these cells.


Development of a Potent, Specific CDK8 Kinase Inhibitor Which Phenocopies CDK8/19 Knockout Cells.,Koehler MF, Bergeron P, Blackwood EM, Bowman K, Clark KR, Firestein R, Kiefer JR, Maskos K, McCleland ML, Orren L, Salphati L, Schmidt S, Schneider EV, Wu J, Beresini MH ACS Med Chem Lett. 2016 Jan 6;7(3):223-8. doi: 10.1021/acsmedchemlett.5b00278., eCollection 2016 Mar 10. PMID:26985305<ref>PMID:26985305</ref>
==See Also==
 
*[[Cyclin 3D structures|Cyclin 3D structures]]
From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
*[[Cyclin-dependent kinase 3D structures|Cyclin-dependent kinase 3D structures]]
</div>
<div class="pdbe-citations 5cei" style="background-color:#fffaf0;"></div>
== References ==
== References ==
<references/>
<references/>
__TOC__
__TOC__
</StructureSection>
</StructureSection>
[[Category: Kiefer, J R]]
[[Category: Homo sapiens]]
[[Category: Koehler, M F.T]]
[[Category: Large Structures]]
[[Category: Maskos, K]]
[[Category: Kiefer JR]]
[[Category: Schneider, E V]]
[[Category: Koehler MFT]]
[[Category: Cdk8]]
[[Category: Maskos K]]
[[Category: Cyclin]]
[[Category: Schneider EV]]
[[Category: Cyclin dependent kinase]]
[[Category: Inhibitor]]
[[Category: Kinase]]
[[Category: Transcription-transferase-inhibitor complex]]
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