Structure of the cyclin-dependent kinase inhibitor p19Ink4d

Frederich Y. Luh, Sharon J. Archer, Peter J. Domaille, Brian O. Smith, Darerca Owen, Deborah H. Brotherton, Andrew R. C. Raine, Xu Xu, Leonardo Brizuela, Stephen L. Brenner and Ernest D. Laue ()
Additional contact information
Frederich Y. Luh: Cambridge Centre for Molecular Recognition, University of Cambridge
Sharon J. Archer: Du Pont Merck Pharmaceutical Company
Peter J. Domaille: Du Pont Merck Pharmaceutical Company
Brian O. Smith: Cambridge Centre for Molecular Recognition, University of Cambridge
Darerca Owen: Cambridge Centre for Molecular Recognition, University of Cambridge
Deborah H. Brotherton: Cambridge Centre for Molecular Recognition, University of Cambridge
Andrew R. C. Raine: Cambridge Centre for Molecular Recognition, University of Cambridge
Xu Xu: Mitotix Inc., One Kendall Square
Leonardo Brizuela: Mitotix Inc., One Kendall Square
Stephen L. Brenner: Du Pont Merck Pharmaceutical Company
Ernest D. Laue: Cambridge Centre for Molecular Recognition, University of Cambridge

Nature, 1997, vol. 389, issue 6654, 999-1003

Abstract: Abstract In cancer, the biochemical pathways that are dominated by the two tumour-suppressor proteins, p53 and Rb, are the most frequently disrupted. Cyclin D-dependent kinases phosphorylate Rb to control its activity and they are, in turn, specifically inhibited by the Ink4 family of cyclin-dependent kinase inhibitors (CDKIs) which cause arrest at the G1 phase of the cell cycle. Mutations in Rb, cyclin D1, its catalytic subunit Cdk4, and the CDKI p16Ink4a, which alter the protein or its level of expression, are all strongly implicated in cancer. This suggests that the Rb ‘pathway’ is of particular importance1. Here we report the structure of the p19Ink4d protein, determined by NMR spectroscopy2,3,4. The structure indicates that most mutations to the p16Ink4a gene, which result in loss of function, are due to incorrectly folded and/or insoluble protein5. We propose a model for the interaction of Ink4 proteins with D-type cyclin-Cdk4/6 complexes that might provide a basis for the design of therapeutics against cancer.

Date: 1997
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DOI: 10.1038/40202

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