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5xqx

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Revision as of 06:57, 14 October 2020

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

Structural highlights

5xqx is a 2 chain structure. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:	,
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

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.

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^[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
↑ Han X, Jiang M, Zhou C, Zhou Z, Xu Z, Wang L, Mayweg AV, Niu R, Jin TG, Yang S. Discovery of potent and selective CDK8 inhibitors through FBDD approach. Bioorg Med Chem Lett. 2017 Aug 1. pii: S0960-894X(17)30787-4. doi:, 10.1016/j.bmcl.2017.07.080. PMID:28802632 doi:http://dx.doi.org/10.1016/j.bmcl.2017.07.080

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/5xqx"

@@ Line 1: / Line 1: @@
 ==Human CDK8-CYCC in complex with compound 4: N-methyl-4-(4-pyridyl)-1H-pyrrole-2-carboxamide==
-<StructureSection load='5xqx' size='340' side='right' caption='[[5xqx]], [[Resolution|resolution]] 2.30&Aring;' scene=''>
+<StructureSection load='5xqx' size='340' side='right'caption='[[5xqx]], [[Resolution|resolution]] 2.30&Aring;' scene=''>
 == Structural highlights ==
-<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>
+<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://proteopedia.org/fgij/fg.htm?mol=5XQX FirstGlance]. <br>
-</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>
+</td></tr><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>
-<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>
+<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://proteopedia.org/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>
 </table>
 == Function ==
@@ Line 18: / Line 18: @@
 </div>
 <div class="pdbe-citations 5xqx" 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: Large Structures]]
 [[Category: Xu, Z H]]
 [[Category: Zhou, Z]]

5xqx

From Proteopedia

Revision as of 06:57, 14 October 2020

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

Structural highlights

Function

Publication Abstract from PubMed

See Also

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

Views

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