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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Acknowledgements
We thank S. Geromanos and H. Erdjument-Bromage of the Sloan-Kettering Microchemistry Facility for N-terminal sequence and mass spectroscopic analyses; H. Chou and E. D. Harlow for baculovirus vectors expressing Cdk6, GST–Cdk6 and cyclin D1; R. Marmorstein for the crystallographic coordinates of p18; C. Ogata of the National Synchrotron Light Source X4A beam line and the staff of the Cornell High Energy Synchrotron Source MacChess for help with data collection; and C. Murray for administrative help. Supported by the Howard Hughes Medical Institute, the NIH, the Pew Charitable Trusts, the Dewitt Wallace Foundation, and the Samuel and May Rudin Foundation.
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Russo, A., Tong, L., Lee, JO. et al. Structural basis for inhibition of the cyclin-dependent kinase Cdk6 by the tumour suppressor p16INK4a. Nature 395, 237–243 (1998). https://doi.org/10.1038/26155
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DOI: https://doi.org/10.1038/26155
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