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Crystal structure of the complex of the cyclin D-dependent kinase Cdk6 bound to the cell-cycle inhibitor p19INK4d

Author

Listed:
  • Deborah H. Brotherton

    (Cambridge Centre for Molecular Recognition, University of Cambridge)

  • Venugopal Dhanaraj

    (Cambridge Centre for Molecular Recognition, University of Cambridge)

  • Scott Wick

    (Mitotix Inc., One Kendall Square, Building 600)

  • Leonardo Brizuela

    (Mitotix Inc., One Kendall Square, Building 600)

  • Peter J. Domaille

    (Du Pont Pharmaceutical Company)

  • Elena Volyanik

    (Cambridge Centre for Molecular Recognition, University of Cambridge)

  • Xu Xu

    (Mitotix Inc., One Kendall Square, Building 600)

  • Emilio Parisini

    (Cambridge Centre for Molecular Recognition, University of Cambridge)

  • Brian O. Smith

    (Cambridge Centre for Molecular Recognition, University of Cambridge)

  • Sharon J. Archer

    (Du Pont Pharmaceutical Company)

  • Manuel Serrano

    (Centro Nacional de Biotecnologia, Campus de Cantoblanco)

  • Stephen L. Brenner

    (Du Pont Pharmaceutical Company)

  • Tom L. Blundell

    (Cambridge Centre for Molecular Recognition, University of Cambridge)

  • Ernest D. Laue

    (Cambridge Centre for Molecular Recognition, University of Cambridge)

Abstract

The crystal structure of the cyclin D-dependent kinase Cdk6 bound to the p19INK4d protein has been determined at 1.9 Å resolution. The results provide the first structural information for a cyclin D-dependent protein kinase and show how the INK4 family of CDK inhibitors bind. The structure indicates that the conformational changes induced by p19INK4d inhibit both productive binding of ATP and the cyclin-induced rearrangement of the kinase from an inactive to an active conformation. The structure also shows how binding of an INK4 inhibitor would prevent binding of p27Kip1, resulting in its redistribution to other CDKs. Identification of the critical residues involved in the interaction explains how mutations in Cdk4 and p16INK4a result in loss of kinase inhibition and cancer.

Suggested Citation

  • Deborah H. Brotherton & Venugopal Dhanaraj & Scott Wick & Leonardo Brizuela & Peter J. Domaille & Elena Volyanik & Xu Xu & Emilio Parisini & Brian O. Smith & Sharon J. Archer & Manuel Serrano & Stephe, 1998. "Crystal structure of the complex of the cyclin D-dependent kinase Cdk6 bound to the cell-cycle inhibitor p19INK4d," Nature, Nature, vol. 395(6699), pages 244-250, September.
    • Handle: RePEc:nat:nature:v:395:y:1998:i:6699:d:10.1038_26164
    DOI: 10.1038/26164
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