Crystal structure of the complex of the cyclin D-dependent kinase Cdk6 bound to the cell-cycle inhibitor p19INK4d

Brotherton, Deborah H.; Dhanaraj, Venugopal; Wick, Scott; Brizuela, Leonardo; Domaille, Peter J.; Volyanik, Elena; Xu, Xu; Parisini, Emilio; Smith, Brian O.; Archer, Sharon J.; Serrano, Manuel; Brenner, Stephen L.; Blundell, Tom L.; Laue, Ernest D.

doi:10.1038/26164

Cited by 210Cancer-related Molecular PathwaysProtein Kinase Regulation and GTPase SignalingEnzyme Structure and Function

Crystal structure of the complex of the cyclin D-dependent kinase Cdk6 bound to the cell-cycle inhibitor p19INK4d

Brotherton, Deborah H., Dhanaraj, Venugopal, Wick, Scott, Brizuela, Leonardo, Domaille, Peter J., Volyanik, Elena, Xu, Xu, Parisini, Emilio +6 more·1998·Nature

DOI 10.1038/26164

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Abstract

The crystal structure of the cyclin D-dependent kinase Cdk6 bound to the p19 INK4d protein has been determined at 1.9 A resolution. The results provide the first structural information for a cyclin D-dependent protein kinase and show how the INK4 family of CDK inhibitors bind. The structure indicates that the conformational changes induced by p19INK4d inhibit both productive binding of ATP and the cyclin-induced rearrangement of the kinase from an inactive to an active conformation. The structure also shows how binding of an INK4 inhibitor would prevent binding of p27Kip1, resulting in its redistribution to other CDKs. Identification of the critical residues involved in the interaction explains how mutations in Cdk4 and p16INK4a result in loss of kinase inhibition and cancer.

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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 Brotherton 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 Brotherton et al , 1998

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Crystal structure and mutational analysis of cell cycle regulator, p18(INK4c)
Venkataramani, R. (2001) · Scholarly Commons (University of Pennsylvania)

Authors: Brotherton, D. H., Dhanaraj, V., Wick, S., Brizuela, L., Domaille, P. J., Volyanik, E., Xu, X., Parisini, E., Smith, B. O., Archer, S. J., Serrano, M., Brenner, S. L., Blundell, T. L., & Laue, E. D.
Affiliations: University of Cambridge (GB)
DuPont (United States) (US)
Centro Nacional de Biotecnología (ES)
Corresponding author: Laue, Ernest D.
ORCID: Brotherton, Deborah H.
Wick, Scott
Xu, Xu
Parisini, Emilio
Smith, Brian O.
Serrano, Manuel
Blundell, Tom L.
Laue, Ernest D.
Venue: Nature
Publisher: Springer Science and Business Media LLC
Published: 1998-09
Volume: 395
Issue: 6699
Pages: 244-250
ISSN: 0028-0836 (ISSN-L)
1476-4687
DOI: 10.1038/26164
OpenAlex: W1622452956
Cited by: 210
References: 49
Citations by year: 2025: 5 · 2024: 4 · 2023: 1 · 2022: 4 · 2021: 2 · 2020: 6 · 2019: 4 · 2018: 2 · 2017: 3 · 2016: 2 · 2015: 3 · 2014: 4 · 2013: 4 · 2012: 5
FWCI: 9.06
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)
Funders: Wellcome Trust
Topics: Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
Physical Sciences › Materials Science › Materials Chemistry › Enzyme Structure and Function
Keywords: CDK6, p19INK4d, cyclin-dependent kinase inhibitors, kinase inhibition mechanism, ATP binding, p27, cell cycle regulation, p16INK4a, cancer
MeSH terms: Adenosine Triphosphate, Amino Acid Sequence, Animals, Binding, Competitive, Carrier Proteins, Catalysis, Cell Line, Escherichia coli, Humans, Insecta, Molecular Sequence Data, Protein Conformation, Recombinant Proteins, Protein Serine-Threonine Kinases, Sequence Homology, Amino Acid, Crystallography, X-Ray, Cell Cycle Proteins, Cyclin-Dependent Kinases, Cyclin-Dependent Kinase Inhibitor p16, Cyclin-Dependent Kinase Inhibitor p19, Cyclin-Dependent Kinase 6, Mice

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Crystal structure of the complex of the cyclin D-dependent kinase Cdk6 bound to the cell-cycle inhibitor p19INK4d

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