DOI: 10.1101/gad.851100. Structural basis of inhibition of CDK

Structural basis of inhibition of CDK–cyclin complexes by INK4 inhibitors

10.1101/gad.851100

Crossref journal-article

Cold Spring Harbor Laboratory

Genes & Development (246)

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.

Bibliography

Jeffrey, P. D., Tong, L., & Pavletich, N. P. (2000). Structural basis of inhibition of CDKâcyclin complexes by INK4 inhibitors. Genes & Development, 14(24), 3115â3125.

Authors 3

Philip D. Jeffrey (first)
Lily Tong (additional)
Nikola P. Pavletich (additional)

References 40 Referenced 187

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{'key': '2021111419251185000_14.24.3115.13', 'first-page': '1581', 'article-title': 'Evidence for different modes of action of cyclin-dependent kinase inhibitors: p15 and p16 bind to kinases, p21 and p27 bind to cyclins.', 'volume': '11', 'author': 'Hall', 'year': '1995', 'journal-title': 'Oncogene'} / Oncogene / Evidence for different modes of action of cyclin-dependent kinase inhibitors: p15 and p16 bind to kinases, p21 and p27 bind to cyclins. by Hall (1995)
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Dates

Type	When
Created	23 years ago (July 26, 2002, 8 p.m.)
Deposited	3 years, 9 months ago (Nov. 14, 2021, 10:40 p.m.)
Indexed	11 hours, 3 minutes ago (Aug. 21, 2025, 12:42 p.m.)
Issued	24 years, 8 months ago (Dec. 15, 2000)
Published	24 years, 8 months ago (Dec. 15, 2000)
Published Online	24 years, 8 months ago (Dec. 15, 2000)
Published Print	24 years, 8 months ago (Dec. 15, 2000)

Funders 0

None

BibTeX

@article{Jeffrey_2000, title={Structural basis of inhibition of CDK–cyclin complexes by INK4 inhibitors}, volume={14}, ISSN={1549-5477}, url={http://dx.doi.org/10.1101/gad.851100}, DOI={10.1101/gad.851100}, number={24}, journal={Genes & Development}, publisher={Cold Spring Harbor Laboratory}, author={Jeffrey, Philip D. and Tong, Lily and Pavletich, Nikola P.}, year={2000}, month=dec, pages={3115–3125} }

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