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5i5z

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Revision as of 07:06, 3 June 2020

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

Structural highlights

5i5z is a 2 chain structure with sequence from Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:	,
Gene:	CDK8 (HUMAN), CCNC (HUMAN)
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

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] [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.^[3] ^[4]

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^[5]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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
↑ 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
↑ 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. 2,8-Disubstituted-1,6-Naphthyridines and 4,6-Disubstituted-Isoquinolines with Potent, Selective Affinity for CDK8/19. ACS Med Chem Lett. 2016 Mar 28;7(6):573-8. doi: 10.1021/acsmedchemlett.6b00022., eCollection 2016 Jun 9. PMID:27326329 doi:http://dx.doi.org/10.1021/acsmedchemlett.6b00022

1 Structural highlights
2 Function
3 Publication Abstract from PubMed
4 See Also
5 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/5i5z"

@@ Line 1: / Line 1: @@
 ==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]] 2.60&Aring;' scene=''>
+<StructureSection load='5i5z' size='340' side='right'caption='[[5i5z]], [[Resolution|resolution]] 2.60&Aring;' scene=''>
 == 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 [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5I5Z FirstGlance]. <br>
+<table><tr><td colspan='2'>[[5i5z]] 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=5I5Z OCA]. For a <b>guided tour on the structure components</b> use [http://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='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'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5i5z FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5i5z OCA], [http://pdbe.org/5i5z PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5i5z RCSB], [http://www.ebi.ac.uk/pdbsum/5i5z PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5i5z ProSAT]</span></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'>[http://proteopedia.org/fgij/fg.htm?mol=5i5z FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5i5z OCA], [http://pdbe.org/5i5z PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5i5z RCSB], [http://www.ebi.ac.uk/pdbsum/5i5z PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5i5z ProSAT]</span></td></tr>
 </table>
 == Function ==
@@ Line 18: / Line 19: @@
 </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/>
 __TOC__
 </StructureSection>
+[[Category: Human]]
+[[Category: Large Structures]]
 [[Category: Blagg, J]]
 [[Category: Mallinger, A]]

5i5z

From Proteopedia

Revision as of 07:06, 3 June 2020

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

Structural highlights

Function

Publication Abstract from PubMed

See Also

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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