CDK4/cyclin D3

Cyclin-dependent kinase 4 (CDK4) and CDK6 are activated early in the G1 phase of the cell cycle as a result of expression of their cyclin D partners. Growth factor binding to receptors at the cell surface activates specific signalling cascades that culminate in increased transcription of the cyclin D genes. CDK4-cyclin D (and CDK6-cyclin D) complexes then principally phosphorylate the product of the retinoblastoma gene, pRb. CDK-dependent pRb phosphorylation results in dissociation of pRb-transcription regulator complexes and concomitant enhancement of expression of genes whose products are required for G1 progression. CDK4 and CDK6 are not essential genes but they are required for the development of certain types of cells. Deregulation of CDK4/6 activity by amplification of cyclin D or mutation of negative CDK4/CDK6 regulators is a frequent occurrence in a number of cancer types. CDK inhibitors currently in clinical trials target CDK4 and CDK6. 

 

Highlights of our study 

  • CDK4-cyclin D3 structure reveals that cyclin binding may not be sufficient to drive the CDK active site toward an active conformation 

  • The activity of CDK4-cyclin D3 toward pRb family members highly depends on substrate recruitment via cyclin D3 

  • The structural mechanism of CDK4-cyclin D3 activation differs markedly from that of previously studied CDK-cyclin complexes 

Comparison of the structures of monomeric CDK2, CDK4-cyclin D3, and T160pCDK2-cyclin A. The 3 structures are viewed looking down onto the CDK C-terminal domain from the N-terminal domain. (A) Monomeric CDK2. (B) CDK4-cyclin D3. (C) T160pCDK2-cyclin A. The figure highlights the displacement of the CDK4/ cyclin D3 activation segment away from the active conformation present in T160pCDK2/cyclin A and its similarity to the structure of the activation segment in monomeric CDK2 (monomeric T160pCDK2 PDB ID code 1HCK). 

Collaborator:  Tim Hunt    

PDB entry: 3G33 

Associated publications: The structure of CDK4/cyclin D3 has implications for models of CDK activation, (2009) Takaki et al., Proc. Natl Acad. Sci. 106: 4171-4176.  

 

 Crystal structure of CDK4/cyclin D3

Crystal structure of CDK4/cyclin D3

 PDB entries: 3G33