5BNJ: Cdk8/cycc In Complex With 8-{3-chloro-5-[4-(1-methyl-1h-pyrazol-4-yl)- Phenyl]-pyridin- 4-yl}-2,8-diaza-spiro[4.5]decan-1-one

There is unmet need for chemical tools to explore the role of the Mediator complex in human pathologies ranging from cancer to cardiovascular disease. Here we determine that CCT251545, a small-molecule inhibitor of the WNT pathway discovered through cell-based screening, is a potent and selective chemical probe for the human Mediator complex-associated protein kinases CDK8 and CDK19 with >100-fold selectivity over 291 other kinases. X-ray crystallography demonstrates a type 1 binding mode involving insertion of the CDK8 C terminus into the ligand binding site. In contrast to type II inhibitors of CDK8 and CDK19, CCT251545 displays potent cell-based activity. We show that CCT251545 and close analogs alter WNT pathway-regulated gene expression and other on-target effects of modulating CDK8 and CDK19, including expression of genes regulated by STAT1. Consistent with this, we find that phosphorylation of STAT1(SER727) is a biomarker of CDK8 kinase activity in vitro and in vivo. Finally, we demonstrate in vivo activity of CCT251545 in WNT-dependent tumors.
PDB ID: 5BNJDownload
MMDB ID: 133332
PDB Deposition Date: 2015/5/26
Updated in MMDB: 2015/11
Experimental Method:
x-ray diffraction
Resolution: 2.64  Å
Source Organism:
Similar Structures:
Biological Unit for 5BNJ: dimeric; determined by software (PISA)
Molecular Components in 5BNJ
Label Count Molecule
Proteins (2 molecules)
Cyclin-dependent Kinase 8(Gene symbol: CDK8)
Molecule annotation
Cyclin-c(Gene symbol: CCNC)
Molecule annotation
Chemicals (3 molecules)
* Click molecule labels to explore molecular sequence information.

Citing MMDB