Structural basis of inhibition of CDK-cyclin complexes by INK4 inhibitors Journal Article
| Authors: | Jeffrey, P. D.; Tong, L.; Pavletich, N. P. |
| Article Title: | Structural basis of inhibition of CDK-cyclin complexes by INK4 inhibitors |
| Abstract: | The cyclin-dependent kinases 4 and 6 (Cdk4/6) that drive progression through the G1 phase of the cell cycle play a central role in the control of cell proliferation, and CDK deregulation is a frequent event in cancer. Cdk4/6 are regulated by the D-type cyclins, which bind to CDKs and activate the kinase, and by the INK4 family of inhibitors. INK4 proteins can bind both monomeric CDK, preventing its association with a cyclin, and also the CDK-cyclin complex, forming an inactive ternary complex. In vivo, binary INK4-Cdk4/6 complexes are more abundant than ternary INK4-Cdk4/6-cyclinD complexes, and it has been suggested that INK4 binding may lead to the eventual dissociation of the cyclin. Here we present the 2.9-Å crystal structure of the inactive ternary complex between Cdk6, the INK4 inhibitor p18INK4c, and a D-type viral cyclin. The structure reveals that p18INK4c inhibits the CDK-cyclin complex by distorting the ATP binding site and misaligning catalytic residues, p18INK4c also distorts the cyclin-binding site, with the cyclin remaining bound at an interface that is substantially reduced in size. These observations support the model that INK4 binding weakens the cyclin's affinity for the CDK. This structure also provides insights into the specificity of the D-type cyclins for Cdk4/6. |
| Keywords: | unclassified drug; proto-oncogene proteins; protein conformation; cell cycle proteins; cell cycle; enzyme inhibition; phosphorylation; enzyme inhibitors; protein-serine-threonine kinases; carrier proteins; tumor suppressor proteins; binding site; crystal structure; models, molecular; crystallography, x-ray; binding sites; adenosine triphosphate; cycline; enzyme specificity; cyclin-dependent kinases; cyclin dependent kinase; cyclin dependent kinase inhibitor; catalytic domain; cyclin-dependent kinase 4; enzyme conformation; cyclin dependent kinase 6; cyclin-dependent kinase 6; cyclin-dependent kinase inhibitor p18; viral cyclin; cdk6; priority journal; article; ink4; cdk inhibition; ink4 inhibitor |
| Journal Title: | Genes and Development |
| Volume: | 14 |
| Issue: | 24 |
| ISSN: | 0890-9369 |
| Publisher: | Cold Spring Harbor Laboratory Press |
| Date Published: | 2000-12-15 |
| Start Page: | 3115 |
| End Page: | 3125 |
| Language: | English |
| DOI: | 10.1101/gad.851100 |
| PUBMED: | 11124804 |
| PROVIDER: | scopus |
| PMCID: | PMC317144 |
| DOI/URL: | |
| Notes: | Export Date: 18 November 2015 -- Source: Scopus |
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