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

• Published in: Nature (London) 1998-09, Vol.395 (6699), p.244-250
• Main Authors: Brotherton, Deborah H., Dhanaraj, Venugopal, Wick, Scott, Brizuela, Leonardo, Domaille, Peter J., Volyanik, Elena, Xu, Xu, Parisini, Emilio, Smith, Brian O., Archer, Sharon J., Serrano, Manuel, Brenner, Stephen L., Blundell, Tom L., Laue, Ernest D.
• Format: Article
• Language: English
• Subjects: Adenosine Triphosphate - metabolism; Amino Acid Sequence; Animals; Binding, Competitive; Biochemistry; Biophysique moleculaire; Cancer; Carrier Proteins - chemistry; Carrier Proteins - metabolism; Catalysis; Cell Cycle Proteins; Cell Line; Crystallography, X-Ray; Crystals; Cyclin-Dependent Kinase 6; Cyclin-Dependent Kinase Inhibitor p16; Cyclin-Dependent Kinase Inhibitor p19; Cyclin-Dependent Kinases; Escherichia coli; Humanities and Social Sciences; Humans; Insecta; Interactions. Associations; Mice; Molecular Sequence Data; multidisciplinary; Mutation; Phénomènes intermoléculaires; Protein Conformation; Protein-Serine-Threonine Kinases - chemistry; Protein-Serine-Threonine Kinases - metabolism; Proteins; Recombinant Proteins - chemistry; Recombinant Proteins - metabolism; Science; Science (multidisciplinary); Sciences biologiques et medicales; Sciences biologiques fondamentales et appliquees. Psychologie; Sequence Homology, Amino Acid; Structure cristalline; Structure en biologie moléculaire
• ISSN: 0028-0836; 1476-4687
• DOI: 10.1038/26164

The crystal structure of the cyclin D-dependent kinase Cdk6 bound to the p19 INK4d 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 p19 INK4d 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 p27 Kip1 , resulting in its redistribution to other CDKs. Identification of the critical residues involved in the interaction explains how mutations in Cdk4 and p16 INK4a result in loss of kinase inhibition and cancer.