Crystal structure of human CDK4 in complex with a D-type cyclin
Philip J Day1, Anne Cleasby, Ian J Tickle
1Astex Therapeutics Ltd., 436 Cambridge Science Park, Milton Road, Cambridge CB4 0QA, United Kingdom.
Summary
Researchers determined the crystal structure of the cyclin D1-cyclin-dependent kinase 4 (CDK4) complex. This structure reveals CDK4 in an inactive state, suggesting a unique regulatory mechanism for this key cell cycle protein.
Area of Science:
- Biochemistry
- Molecular Biology
- Structural Biology
Background:
- The cyclin D1-cyclin-dependent kinase 4 (CDK4) complex regulates cell cycle G1 phase progression.
- Aberrant CDK4/cyclin D1 pathway regulation is implicated in multiple tumor types, making CDK4 a therapeutic target.
- Determining the CDK4/cyclin D1 complex structure has been challenging.
Purpose of the Study:
- To determine the crystal structure of the CDK4/cyclin D1 complex.
- To elucidate the structural basis of CDK4 regulation and activation.
Main Methods:
- X-ray crystallography
- Structure determination at 2.3 A resolution
Main Results:
- The crystal structure of CDK4 in complex with cyclin D1 was determined.
- CDK4 was observed in an inactive conformation despite binding cyclin D1 and having a phosphorylated T-loop.
- The heterodimer conformation differs from previously characterized CDK/cyclin complexes.
Conclusions:
- The determined structure provides insights into a unique mechanism of CDK4 regulation and activation.
- This structural information can inform the development of targeted therapies for cancers with aberrant CDK4/cyclin D1 pathway activity.
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