The protein p16 (INK4) primarily inhibits:
INK4 family represents dedicated inhibitors of CDK4 and CDK6 distinguishing them from Cip/Kip family that target cyclin E-CDK2 and cyclin A-CDK2. p16INK4a product of CDKN2A locus contains four ankyrin repeats forming elongated structure that binds CDK6 opposite cyclin-binding interface, inducing distortion of ATP-binding pocket and preventing association with cyclin D. Since cyclin D-CDK4/6 is earliest kinase phosphorylating Rb in response to mitogens, its inhibition maintains Rb in hypophosphorylated active repressor state bound to E2F, arresting cell before restriction point. Genetic inactiv
Ref: Sherr & Roberts, Genes & Dev 1999, INK4 Family Biology. Alberts 7th ed., Chapter 20.