Molecular Target Synopsis
Overview
Domains and Structures
Drugs and Clinical Candidates
Druggability
Chemistry
Ligand Efficiency Plot
Pathways
Family Cladogram
Interaction Network
Gene Expression
Gene Copy Number Variation
RNAi
Mutations
Germline Genetics

CDK8 (P49336) - Overview - Molecular Target Synopsis

Protein


CDK8, Cyclin-dependent kinase 8
Enzyme Classification 2.7.11.22
UniProt P49336

Also Known as CDK8_HUMAN, CDK8

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. Component of the Mediator complex, which is composed of MED1, MED4, MED6, MED7, MED8, MED9, MED10, MED11, MED12, MED13, MED13L, MED14, MED15, MED16, MED17, MED18, MED19, MED20, MED21, MED22, MED23, MED24, MED25, MED26, MED27, MED29, MED30, MED31, CCNC, CDK8 and CDC2L6/CDK11. The MED12, MED13, CCNC and CDK8 subunits form a distinct module termed the CDK8 module. Mediator containing the CDK8 module is less active than Mediator lacking this module in supporting transcriptional activation. Individual preparations of the Mediator complex lacking one or more distinct subunits have been variously termed ARC, CRSP, DRIP, PC2, SMCC and TRAP. The cylin/CDK pair formed by CCNC/CDK8 also associates with the large subunit of RNA polymerase II. Interacts with CTNNB1, GLI3 and MAML1.

5XQX
HUMAN CDK8-CYCC IN COMPLEX WITH COMPOUND 4: N-METHYL-4-(4-PYRIDYL)-1H- PYRROLE-2-CARBOXAMIDE
RCSB/PDB
Inspect Structure
See all 3D Structures for CDK8

Isoforms / Transcripts (Protein Coding)


Protein Length Ensembl Gene Ensembl Transcript Ensembl Protein Uniprot Isoform
464ENSG00000132964ENST00000381527ENSP00000370938P49336-1
463P49336-2
164ENSG00000132964ENST00000536792ENSP00000437696

Sub-cellular localization


UniProt: CDK8 is active in the following subcellular-locations: nucleus.
GO terms: CDK8 is active in the following subcellular-locations: mediator complex, nucleolus, nucleoplasm, nucleus, protein-containing complex.



UniProt
GO terms

Gene Copy Number Variation


In COSMIC - Cell Lines Project CDK8 has gain in 4 cell-lines, loss in 5 cell-lines and no signal in 996 cell-lines. (see details)

Gene Expression


In NCI60, the highest expressing cell lines are: HL_60, COLO205, K_562

In Array Express (RNA-seq of 675 commonly used human cancer cell lines), the highest expressing cell lines are: SW 480, SNU-5, TK

In Array Express (RNA-seq of long poly adenylated RNA and long non poly adenylated RNA from ENCODE cell lines), the highest expressing cell lines are: SK-N-SH, HSMM, NHLF

(see details)

RNA Interference


CDK8 was reported in the following RNAI studies:

Cell - Large Scale Profiling of Kinase Dependencies in Cancer Cell Lines, the highest RNAi cell lines are: SKBR3, CROE33. (see details)

3D Structures


For CDK8 there are:
25 structures (25 chains) solved
24 are solved in complex with at least one small molecule ligand
1 are solved with an approved drug

CDK8 is solved in complex with the approved drug(s):

BAX/SORAFENIB (3RGF_A).

(see details)
Molecular Target 3D Synopsis

Screening and Chemistry


CDK8 has been screened with 338 compounds (524 bioactivities), 166 compounds have bioactivities that show binding affinity of <= 500nM (246 bioactivities). (see details)