Structural basis for inhibition of the cyclin-dependent kinase Cdk6 by the tumour suppressor p16INK4a.

The cyclin-dependent kinases 4 and 6 (Cdk4/6) that control the G1 phase of the cell cycle and their inhibitor, the p16INK4a tumour suppressor, have a central role in cell proliferation and in tumorigenesis. The structures of Cdk6 bound to p16INK4a and to the related p19INK4d reveal that the INK4 inhibitors ...
bind next to the ATP-binding site of the catalytic cleft, opposite where the activating cyclin subunit binds. They prevent cyclin binding indirectly by causing structural changes that propagate to the cyclin-binding site. The INK4 inhibitors also distort the kinase catalytic cleft and interfere with ATP binding, which explains how they can inhibit the preassembled Cdk4/6-cyclin D complexes as well. Tumour-derived mutations in INK4a and Cdk4 map to interface contacts, solidifying the role of CDK binding and inhibition in the tumour suppressor activity of p16INK4a.
Mesh Terms:
Adenosine Triphosphate, Amino Acid Sequence, Binding Sites, Carrier Proteins, Cell Cycle Proteins, Crystallography, X-Ray, Cyclin D, Cyclin-Dependent Kinase 6, Cyclin-Dependent Kinase Inhibitor p16, Cyclin-Dependent Kinase Inhibitor p19, Cyclin-Dependent Kinases, Cyclins, Enzyme Inhibitors, Escherichia coli, Genes, Tumor Suppressor, Humans, Models, Molecular, Molecular Sequence Data, Protein Binding, Protein Conformation, Protein-Serine-Threonine Kinases, Recombinant Proteins, Structure-Activity Relationship
Nature
Date: Sep. 17, 1998
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