2.5 Å-resolution structure of human CDK-activating kinase bound to the clinical inhibitor ICEC0942
Basil J Greber1, Jonathan Remis2, Simak Ali3
1Division of Structural Biology, The Institute of Cancer Research, London, United Kingdom; California Institute for Quantitative Biosciences (QB3), University of California, Berkeley, Berkeley, California; Molecular Biophysics and Integrative Bio-Imaging Division, Lawrence Berkeley National Laboratory, Berkeley, California.
Abstract:
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 Å-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.
Insights
Researchers determined the structure of human CDK-activating kinase (CAK) bound to the cancer drug candidate ICEC0942 using cryo-EM. This provides insights for developing more effective cancer therapies targeting cell cycle control.
Area of Science:
- Structural Biology
- Biochemistry
- Cancer Therapeutics
Background:
- The human CDK-activating kinase (CAK), a complex of CDK7, cyclin H, and MAT1, regulates transcription initiation and the cell cycle.
- CAK is a validated target for cancer chemotherapy, with several CDK7 inhibitors, including ICEC0942 (CT7001), currently in clinical trials.
- Understanding the structural basis of drug-target interactions is crucial for optimizing drug affinity, specificity, and minimizing patient side effects.
Purpose of the Study:
- To determine the high-resolution structure of the human CAK in complex with the inhibitor ICEC0942.
- To elucidate the conformational state of ICEC0942 when bound to human CAK.
- To highlight the utility of cryogenic electron microscopy (cryo-EM) for structural studies of drug-bound protein complexes.
Main Methods:
- The study utilized cryogenic electron microscopy (cryo-EM) to resolve the structure.
- The target protein complex was human CAK (CDK7/cyclin H/MAT1).
- The small molecule inhibitor ICEC0942 was used for complex formation.
Main Results:
- The structure of human CAK in complex with ICEC0942 was determined at 2.5 Å resolution.
- Conformational differences of ICEC0942 were observed compared to its structure in complex with CDK2 (determined by X-ray crystallography).
- The cryo-EM structure provides detailed molecular insights into the drug-CAK interaction.
Conclusions:
- The determined cryo-EM structure offers valuable information for the rational design of improved CDK7 inhibitors.
- Cryo-EM is a powerful technique for resolving structures of drug-bound protein complexes, even without the need for crystallization.
- This structural data can guide the development of more effective and specific cancer therapeutics targeting the cell cycle.
Related Concept Videos
02:34Inhibition of Cdk Activity
02:39Positive Regulator Molecules
02:15M-Cdk Drives Transition Into Mitosis
Cyclin-dependent kinases, or Cdks, work in concert with cyclins to control cell cycle transitions. M-Cdk, a complex of Cdk1 bound to M cyclin, is a well-known example of this coordinated control that drives the transition from the G2 to the M phase.
M cyclin...