5xqx

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==Human CDK8-CYCC in complex with compound 4: N-methyl-4-(4-pyridyl)-1H-pyrrole-2-carboxamide==
==Human CDK8-CYCC in complex with compound 4: N-methyl-4-(4-pyridyl)-1H-pyrrole-2-carboxamide==
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<StructureSection load='5xqx' size='340' side='right' caption='[[5xqx]], [[Resolution|resolution]] 2.30&Aring;' scene=''>
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<StructureSection load='5xqx' size='340' side='right'caption='[[5xqx]], [[Resolution|resolution]] 2.30&Aring;' scene=''>
== Structural highlights ==
== Structural highlights ==
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<table><tr><td colspan='2'>[[5xqx]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5XQX OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5XQX FirstGlance]. <br>
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<table><tr><td colspan='2'>[[5xqx]] 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=5XQX OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5XQX 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=8CC:N-methyl-4-pyridin-4-yl-1H-pyrrole-2-carboxamide'>8CC</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene></td></tr>
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</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.3&#8491;</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=5xqx FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5xqx OCA], [http://pdbe.org/5xqx PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5xqx RCSB], [http://www.ebi.ac.uk/pdbsum/5xqx PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5xqx ProSAT]</span></td></tr>
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<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=8CC:N-methyl-4-pyridin-4-yl-1H-pyrrole-2-carboxamide'>8CC</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene></td></tr>
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<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=5xqx FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5xqx OCA], [https://pdbe.org/5xqx PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5xqx RCSB], [https://www.ebi.ac.uk/pdbsum/5xqx PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5xqx ProSAT]</span></td></tr>
</table>
</table>
== Function ==
== 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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[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>
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<div style="background-color:#fffaf0;">
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== Publication Abstract from PubMed ==
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A fragment library screen was carried out to identify starting points for novel CDK8 inhibitors. Optimization of a fragment hit guided by co-crystal structures led to identification of a novel series of potent CDK8 inhibitors which are highly ligand efficient, kinase selective and cellular active. Compound 16 was progressed to a mouse pharmacokinetic study and showed good oral bioavailability.
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Discovery of potent and selective CDK8 inhibitors through FBDD approach.,Han X, Jiang M, Zhou C, Zhou Z, Xu Z, Wang L, Mayweg AV, Niu R, Jin TG, Yang S Bioorg Med Chem Lett. 2017 Aug 1. pii: S0960-894X(17)30787-4. doi:, 10.1016/j.bmcl.2017.07.080. PMID:28802632<ref>PMID:28802632</ref>
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==See Also==
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*[[Cyclin 3D structures|Cyclin 3D structures]]
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From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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*[[Cyclin-dependent kinase 3D structures|Cyclin-dependent kinase 3D structures]]
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</div>
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<div class="pdbe-citations 5xqx" style="background-color:#fffaf0;"></div>
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== References ==
== References ==
<references/>
<references/>
__TOC__
__TOC__
</StructureSection>
</StructureSection>
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[[Category: Xu, Z H]]
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[[Category: Homo sapiens]]
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[[Category: Zhou, Z]]
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[[Category: Large Structures]]
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[[Category: Cdk8]]
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[[Category: Xu ZH]]
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[[Category: Cyclin c]]
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[[Category: Zhou Z]]
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[[Category: Mediator complex]]
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[[Category: Transferase]]
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Current revision

Human CDK8-CYCC in complex with compound 4: N-methyl-4-(4-pyridyl)-1H-pyrrole-2-carboxamide

PDB ID 5xqx

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