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

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, Stephen L. Brenner, Tom L. Blundell and Ernest D. Laue ()
Additional contact information
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

Nature, 1998, vol. 395, issue 6699, 244-250

Abstract: 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.

Date: 1998
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DOI: 10.1038/26164

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