CRYSTAL-STRUCTURE OF THE COMPLEX OF THE CYCLIN-D DEPENDENT KINASE CDK6 BOUND TO THE CELL-CYCLE INHIBITOR P19(INK4D)

The crystal structure of the cyclin D-dependent kinase Cdk6 bound to t he p19(INK4d) protein has been determined at 1.9 Angstrom resolution. The results provide the first structural Information for a cyclin D-de pendent 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-in duced rearrangement of the kinase from an Inactive to an active confor mation. The structure also shows how binding of an INK4 inhibitor woul d prevent binding of p27(Kip1), resulting In Its redistribution to oth er CDKs. identification of the critical residues involved in the Inter action explains how mutations in Cdk4 and p16(INK4a) result in loss of kinase inhibition and cancer.