5CEI: Crystal Structure Of Cdk8:cyclin C Complex With Compound 22

Beginning with promiscuous COT inhibitors, which were found to inhibit CDK8, a series of 6-aza-benzothiophene containing compounds were developed into potent, selective CDK8 inhibitors. When cocrystallized with CDK8 and cyclin C, these compounds exhibit an unusual binding mode, making a single hydrogen bond to the hinge residue A100, a second to K252, and a key cation-pi interaction with R356. Structure-based drug design resulted in tool compounds 13 and 32, which are highly potent, kinase selective, permeable compounds with a free fraction >2% and no measurable efflux. Despite these attractive properties, these compounds exhibit weak antiproliferative activity in the HCT-116 colon cancer cell line. Further examination of the activity of 32 in this cell line revealed that the compound reduced phosphorylation of the known CDK8 substrate STAT1 in a manner identical to a CDK8 knockout clone, illustrating the complex effects of inhibition of CDK8 kinase activity in proliferation in these cells.
PDB ID: 5CEIDownload
MMDB ID: 136384
PDB Deposition Date: 2015/7/6
Updated in MMDB: 2016/05
Experimental Method:
x-ray diffraction
Resolution: 2.24  Å
Source Organism:
Similar Structures:
Biological Unit for 5CEI: dimeric; determined by author and by software (PISA)
Molecular Components in 5CEI
Label Count Molecule
Proteins (2 molecules)
Cyclin-dependent Kinase 8(Gene symbol: CDK8)
Molecule annotation
Cyclin-c(Gene symbol: CCNC)
Molecule annotation
Chemicals (16 molecules)
* Click molecule labels to explore molecular sequence information.

Citing MMDB