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

Author

Listed:
  • 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)

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.

Suggested Citation

  • Alicia A. Russo & Lily Tong & Jie-Oh Lee & Philip D. Jeffrey & Nikola P. Pavletich, 1998. "Structural basis for inhibition of the cyclin-dependent kinase Cdk6 by the tumour suppressor p16INK4a," Nature, Nature, vol. 395(6699), pages 237-243, September.
    • Handle: RePEc:nat:nature:v:395:y:1998:i:6699:d:10.1038_26155
    DOI: 10.1038/26155
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