Structural basis for inhibition of the cyclin-dependent kinase Cdk6 by the tumour suppressor p16INK4a

Russo, Alicia A.; Tong, Lily; Lee, Jie-Oh; Jeffrey, Philip D.; Pavletich, Nikola P.

doi:10.1038/26155

Cited by 524Cancer-related Molecular PathwaysProtein Kinase Regulation and GTPase SignalingMicrotubule and mitosis dynamics

Structural basis for inhibition of the cyclin-dependent kinase Cdk6 by the tumour suppressor p16INK4a

Russo, Alicia A., Tong, Lily, Lee, Jie-Oh, Jeffrey, Philip D., Pavletich, Nikola P.·1998·Nature

DOI 10.1038/26155

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Abstract

The cyclin-dependent kinases 4 and 6 (Cdk4/6) that control the G1 phase of the cell cycle and their inhibitor, the p16INK4a tumour suppressor, have a central role in cell proliferation and in tumorigenesis. The structures of Cdk6 bound to p16INK4a and to the related p19INK4d reveal that the INK4 inhibitors bind next to the ATP-binding site of the catalytic cleft, opposite where the activating cyclin subunit binds. They prevent cyclin binding indirectly by causing structural changes that propagate to the cyclin-binding site. The INK4 inhibitors also distort the kinase catalytic cleft and interfere with ATP binding, which explains how they can inhibit the preassembled Cdk4/6-cyclin D complexes as well. Tumour-derived mutations in INK4a and Cdk4 map to interface contacts, solidifying the role of CDK binding and inhibition in the tumour suppressor activity of p16INK4a.

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The same kind of ATP-binding-site distortion has been seen in CDK6 crystals bound to p16INK4a or p19INK4d.
“A similar structural distortion of the ATP-binding site has been reported in the crystal structure of CDK6 bound to the tumor suppressor p16 INK4a or p19 INK4d (Brotherton et al , 1998; Russo et al , 1998).”
From Structural basis for the selective inhibition of JNK1 by the scaffolding protein JIP1 and SP600125 (2004) · cites this paper as Russo et al , 1998
In CDK6, INK4 inhibitors occupy a site adjacent to the ATP pocket, opposite the activating cyclin, and indirectly block cyclin binding while lowering ATP affinity through allosteric changes.
“In the structure, the INK4 inhibitors bind next to the ATP-binding site, opposite where the activating cyclin binds, and thereby not only prevent cyclin binding indirectly but also reduce the affinity of the kinase for ATP by causing extensive allosteric changes in CDK6.”
From Structural basis for the selective inhibition of JNK1 by the scaffolding protein JIP1 and SP600125 (2004) · cites this paper as Russo et al , 1998

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Authors: Russo, A. A., Tong, L., Lee, J.-O., Jeffrey, P. D., & Pavletich, N. P.
Affiliations: Memorial Sloan Kettering Cancer Center (US)
Corresponding author: Pavletich, Nikola P.
ORCID: Tong, Lily
Lee, Jie-Oh
Jeffrey, Philip D.
Pavletich, Nikola P.
Venue: Nature
Publisher: Springer Science and Business Media LLC
Published: 1998-09
Volume: 395
Issue: 6699
Pages: 237-243
ISSN: 0028-0836 (ISSN-L)
1476-4687
DOI: 10.1038/26155
OpenAlex: W1525531613
Cited by: 524
References: 50
Citations by year: 2026: 7 · 2025: 11 · 2024: 26 · 2023: 16 · 2022: 18 · 2021: 16 · 2020: 17 · 2019: 19 · 2018: 11 · 2017: 9 · 2016: 12 · 2015: 18 · 2014: 15 · 2013: 14 · 2012: 24
FWCI: 13.30
Type: journal article
Language: en
Open access: closed
Licence: www.springer.com/tdm (tdm)
Locations: Nature (publishedVersion)
PubMed (publishedVersion)
RePEc: Research Papers in Economics (submittedVersion)
Topics: Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Microtubule and mitosis dynamics
Keywords: CDK6, p16INK4a, p19INK4d, cyclin-dependent kinase inhibition, ATP binding site, G1 cell cycle regulation, tumour suppressor, protein-protein interfaces
MeSH terms: Adenosine Triphosphate, Amino Acid Sequence, Binding Sites, Carrier Proteins, Enzyme Inhibitors, Escherichia coli, Humans, Models, Molecular, Molecular Sequence Data, Protein Binding, Protein Conformation, Recombinant Proteins, Structure-Activity Relationship, Genes, Tumor Suppressor, Cyclins, Protein Serine-Threonine Kinases, Crystallography, X-Ray, Cell Cycle Proteins, Cyclin-Dependent Kinases, Cyclin-Dependent Kinase Inhibitor p16, Cyclin-Dependent Kinase Inhibitor p19, Cyclin-Dependent Kinase 6, Cyclin D

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Structural basis for inhibition of the cyclin-dependent kinase Cdk6 by the tumour suppressor p16INK4a

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