STRUCTURAL BASIS FOR INHIBITION OF THE CYCLIN-DEPENDENT KINASE CDK6 BY THE TUMOR-SUPPRESSOR P16(INK4A)

The cyclin-dependent kinases 4 and 6 (Cdk4/6) that control the G1 phas e of the cell cycle and their inhibitor, the p16(INK4a) tumour suppres sor, have a central role in cell proliferation and in tumorigenesis. T he structures of Cdk6 bound to p16(INK4a) and to the related p19(INK4d ) reveal that the INK4 inhibitors bind next to the ATP-binding site of the catalytic cleft, opposite where the activating cyclin subunit bin ds. They prevent cyclin binding indirectly by causing structural chang es that propagate to the cyclin-binding site. The INK4 inhibitors also distort the kinase catalytic cleft and interfere with ATP binding, wh ich explains how they can inhibit the preassembled Cdk4/6-cyclin D com plexes as well. Ttrmour-derived mutations in INK4a and Cdk4 map to int erface contacts, solidifying the role of CDK binding and inhibition in the tumour suppressor activity of p16(INK4a).