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Updated: Aug 23, 2025
A Guide to Production, Crystallization, and Structure Determination of Human IKK1/α
Published on: November 2, 2018
Crystal structure of the CDK11 kinase domain bound to the small-molecule inhibitor OTS964
Susan Kelso1, Siobhan O'Brien2, Igor Kurinov3
1Lunenfeld-Tanenbaum Research Institute, Sinai Health System, Toronto, ON M5G 1X5, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A8, Canada.
Abstract:
CDK11 is a cyclin-dependent kinase that controls proliferation by regulating transcription, RNA splicing, and the cell cycle. As its activity is increasingly associated with cancer, CDK11 is an attractive target for the development of small-molecule inhibitors. However, the development of CDK11 inhibitors with limited off-target effects against other CDKs poses a challenge based on the high conservation of sequence across family members. OTS964 is notable as it displays a measure of specificity for CDK11 in cells. To understand the basis for OTS964's specificity for CDK11, we solved a 2.6 Å crystal structure of the CDK11 kinase domain bound to OTS964. Despite the absence of cyclin, CDK11 adopts an active-like conformation when bound to OTS964. We identified amino acids likely to contribute to the specificity of OTS964 for CDK11 and assessed their contribution to OTS964 binding by isothermal titration calorimetry (ITC) in vitro and by resistance to OTS964 in cells.
Insights
Cyclin-dependent kinase 11 (CDK11) inhibitors are promising cancer therapeutics. Researchers elucidated the structural basis for OTS964
Area of Science:
- Molecular Biology
- Structural Biology
- Cancer Research
Background:
- Cyclin-dependent kinase 11 (CDK11) regulates key cellular processes like transcription and cell cycle progression.
- CDK11 activity is implicated in various cancers, making it a therapeutic target.
- Developing specific CDK11 inhibitors is challenging due to high sequence homology with other cyclin-dependent kinases (CDKs).
Purpose of the Study:
- To understand the molecular basis for the specificity of the small-molecule inhibitor OTS964 towards CDK11.
- To investigate the structural interactions between OTS964 and the CDK11 kinase domain.
Main Methods:
- X-ray crystallography was used to determine the 2.6 Å crystal structure of the CDK11 kinase domain bound to OTS964.
- Isothermal titration calorimetry (ITC) was employed for in vitro binding assays.
- Cell-based assays were used to assess resistance to OTS964.
Main Results:
- The crystal structure revealed that CDK11 adopts an active-like conformation upon binding to OTS964, even without its cyclin partner.
- Specific amino acid residues contributing to OTS964's selectivity for CDK11 were identified.
- In vitro and cellular assays confirmed the contribution of these residues to OTS964 binding and efficacy.
Conclusions:
- The study provides a structural understanding of OTS964's specificity for CDK11.
- This knowledge can guide the design of more selective CDK11 inhibitors for cancer therapy.
- The identified structural features are crucial for developing targeted therapies with reduced off-target effects.
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