The crystal structure of the cyclin D-dependent kinase Cdk6 bound to the p19(INK4d) protein has been determined at 1.9 Angstrom 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.