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Toward understanding the structural basis of cyclin-dependent kinase 6 specific inhibition
Heshu Lu1, Ursula Schulze-Gahmen
1Physical Biosciences Division at Lawrence Berkeley National Laboratory, 1 Cyclotron Road, MS3, Berkeley, California, USA.
Abstract:
Cyclin-dependent kinases (CDKs) are key players in cell cycle control, and genetic alterations of CDKs and their regulators have been linked to a variety of cancers. Hence, CDKs are obvious targets for therapeutic intervention in various proliferative diseases, including cancer. To date, drug design efforts have mostly focused on CDK2 because methods for crystallization of its inhibitor complexes have been well established. CDK4 and CDK6, however, may be at least as important as enzymes for cell cycle regulation and could provide alternative treatment options. We describe here two complex structures of human CDK6 with a very specific kinase inhibitor, PD0332991, which is based on a pyrido[2,3-d]pyrimidin-7-one scaffold, and with the less specific aminopurvalanol inhibitor. Analysis of the structures suggests that relatively small conformational differences between CDK2 and CDK6 in the hinge region are contributing to the inhibitor specificity by inducing changes in the inhibitor orientation that lead to sterical clashes in CDK2 but not CDK6. These complex structures provide valuable insights for the future development of CDK-specific inhibitors.
Insights
Cyclin-dependent kinases (CDKs) regulate cell division and are cancer targets. Structural analysis of CDK6 with inhibitors reveals key differences from CDK2, guiding the development of more specific cancer drugs.
Area of Science:
- Biochemistry
- Molecular Biology
- Structural Biology
Background:
- Cyclin-dependent kinases (CDKs) are crucial for cell cycle control.
- Genetic alterations in CDKs are implicated in various cancers, making them therapeutic targets.
- Current drug design primarily targets CDK2 due to established crystallization methods.
Purpose of the Study:
- To elucidate the structural basis of inhibitor specificity for CDK6.
- To provide insights for developing novel CDK-specific inhibitors for cancer therapy.
Main Methods:
- X-ray crystallography was used to determine the complex structures of human CDK6.
- Two inhibitors were studied: PD0332991 (specific) and aminopurvalanol (less specific).
Main Results:
- Detailed structures of CDK6 in complex with PD0332991 and aminopurvalanol were obtained.
- Small conformational differences in the hinge region between CDK2 and CDK6 influence inhibitor binding.
- These differences explain the specificity of PD0332991 for CDK6 over CDK2 due to steric clashes.
Conclusions:
- Structural insights into CDK6-inhibitor complexes are crucial for drug development.
- Targeting CDK6 offers a promising alternative therapeutic strategy for proliferative diseases.
- Understanding CDK conformational nuances enables the design of highly specific kinase inhibitors.
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