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

Alicia A. Russo, Lily Tong, Jie-Oh Lee, Philip D. Jeffrey and Nikola P. Pavletich ()
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Alicia A. Russo: Cellular Biochemistry and Biophysics Program
Lily Tong: Howard Hughes Medical Institute, Memorial Sloan-Kettering Cancer Center
Jie-Oh Lee: Howard Hughes Medical Institute, Memorial Sloan-Kettering Cancer Center
Philip D. Jeffrey: Cellular Biochemistry and Biophysics Program
Nikola P. Pavletich: Howard Hughes Medical Institute, Memorial Sloan-Kettering Cancer Center

Nature, 1998, vol. 395, issue 6699, 237-243

Abstract: 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.

Date: 1998
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DOI: 10.1038/26155

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