5i5z
From Proteopedia
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==CDK8-CYCC IN COMPLEX WITH 8-(1-Methyl-2,2-dioxo-2,3-dihydro-1H-2l6-benzo[c]isothiazol-5-yl)-[1,6]naphthyridine-2-carboxylic acid methylamide== | ==CDK8-CYCC IN COMPLEX WITH 8-(1-Methyl-2,2-dioxo-2,3-dihydro-1H-2l6-benzo[c]isothiazol-5-yl)-[1,6]naphthyridine-2-carboxylic acid methylamide== | ||
| - | <StructureSection load='5i5z' size='340' side='right' caption='[[5i5z]], [[Resolution|resolution]] 2.60Å' scene=''> | + | <StructureSection load='5i5z' size='340' side='right'caption='[[5i5z]], [[Resolution|resolution]] 2.60Å' scene=''> |
== Structural highlights == | == Structural highlights == | ||
| - | <table><tr><td colspan='2'>[[5i5z]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5I5Z OCA]. For a <b>guided tour on the structure components</b> use [ | + | <table><tr><td colspan='2'>[[5i5z]] 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=5I5Z OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5I5Z FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=68U:N-METHYL-8-(1-METHYL-2,2-DIOXO-2,3-DIHYDRO-1H-2LAMBDA~6~,1-BENZOTHIAZOL-5-YL)-1,6-NAPHTHYRIDINE-2-CARBOXAMIDE'>68U</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]] 2.6Å</td></tr> |
| - | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[ | + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=68U:N-METHYL-8-(1-METHYL-2,2-DIOXO-2,3-DIHYDRO-1H-2LAMBDA~6~,1-BENZOTHIAZOL-5-YL)-1,6-NAPHTHYRIDINE-2-CARBOXAMIDE'>68U</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'>[https://proteopedia.org/fgij/fg.htm?mol=5i5z FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5i5z OCA], [https://pdbe.org/5i5z PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5i5z RCSB], [https://www.ebi.ac.uk/pdbsum/5i5z PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5i5z ProSAT]</span></td></tr> | ||
</table> | </table> | ||
== Function == | == Function == | ||
| - | [ | + | [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 == | ||
| + | We demonstrate a designed scaffold-hop approach to the discovery of 2,8-disubstituted-1,6-naphthyridine- and 4,6-disubstituted-isoquinoline-based dual CDK8/19 ligands. Optimized compounds in both series exhibited rapid aldehyde oxidase-mediated metabolism, which could be abrogated by introduction of an amino substituent at C5 of the 1,6-naphthyridine scaffold or at C1 of the isoquinoline scaffold. Compounds 51 and 59 were progressed to in vivo pharmacokinetic studies, and 51 also demonstrated sustained inhibition of STAT1(SER727) phosphorylation, a biomarker of CDK8 inhibition, in an SW620 colorectal carcinoma human tumor xenograft model following oral dosing. | ||
| + | |||
| + | 2,8-Disubstituted-1,6-Naphthyridines and 4,6-Disubstituted-Isoquinolines with Potent, Selective Affinity for CDK8/19.,Mallinger A, Schiemann K, Rink C, Sejberg J, Honey MA, Czodrowski P, Stubbs M, Poeschke O, Busch M, Schneider R, Schwarz D, Musil D, Burke R, Urbahns K, Workman P, Wienke D, Clarke PA, Raynaud FI, Eccles SA, Esdar C, Rohdich F, Blagg J ACS Med Chem Lett. 2016 Mar 28;7(6):573-8. doi: 10.1021/acsmedchemlett.6b00022., eCollection 2016 Jun 9. PMID:27326329<ref>PMID:27326329</ref> | ||
| + | |||
| + | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | ||
| + | </div> | ||
| + | <div class="pdbe-citations 5i5z" 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: | + | [[Category: Homo sapiens]] |
| - | [[Category: | + | [[Category: Large Structures]] |
| - | [[Category: | + | [[Category: Blagg J]] |
| - | [[Category: | + | [[Category: Mallinger A]] |
| - | [[Category: | + | [[Category: Musil D]] |
Current revision
CDK8-CYCC IN COMPLEX WITH 8-(1-Methyl-2,2-dioxo-2,3-dihydro-1H-2l6-benzo[c]isothiazol-5-yl)-[1,6]naphthyridine-2-carboxylic acid methylamide
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