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.
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Acknowledgements
We thank C. J. Sherr for the plasmid expressing GST-p19Ink4d; S. Ishii for plasmids expressing GroEL and GroES; W. Boucher for computer programming; M. Nilges for protocols for the structure calculations; J. Krywko for the model of Cdk4; M. Serrano and D. Beach for assaying p19Ink4d and for communicating unpublished results; N. Pavletich for the coordinates of 53BP2; and A. Murzin for helpful discussion. This work was supported by a grant from the BBSRC. The Cambridge Centre for Molecular Recognition is supported by the BBSRC and the Wellcome Trust.
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Luh, F., Archer, S., Domaille, P. et al. Structure of the cyclin-dependent kinase inhibitor p19Ink4d. Nature 389, 999–1003 (1997). https://doi.org/10.1038/40202
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DOI: https://doi.org/10.1038/40202
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