2.5 Å-resolution structure of human CDK-activating kinase bound to the clinical inhibitor ICEC0942

The human CDK-activating kinase (CAK), composed of CDK7, cyclin H, and MAT1, is involved in the control of transcription initiation and the cell cycle. Because of these activities, it has been identified as a promising target for cancer chemotherapy. A number of CDK7 inhibitors have entered clinical trials, among them ICEC0942 (also known as CT7001). Structural information can aid in improving the affinity and specificity of such drugs or drug candidates, reducing side effects in patients. Here, we have determined the structure of the human CAK in complex with ICEC0942 at 2.5 angstrom-resolution using cryogenic electron microscopy. Our structure reveals conformational differences of ICEC0942 compared with previous X-ray crystal structures of the CDK2-bound complex, and highlights the critical ability of cryogenic electron microscopy to resolve structures of drug-bound protein complexes without the need to crystalize the protein target.

Automated summary

The human CDK-activating kinase (CAK) is a promising target for cancer chemotherapy due to its role in transcription initiation and cell cycle control. A study used cryogenic electron microscopy to determine the structure of human CAK in complex with ICEC0942, revealing conformational differences with previous X-ray crystal structures of CDK2-bound complex. This demonstrates the critical ability of cryogenic electron microscopy in resolving structures of drug-bound protein complexes without the need for protein crystallization.