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

Nature. 1998 Sep 17;395(6699):237-43. doi: 10.1038/26155.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Adenosine Triphosphate / metabolism
  • Amino Acid Sequence
  • Binding Sites
  • Carrier Proteins / chemistry
  • Carrier Proteins / metabolism
  • Cell Cycle Proteins*
  • Crystallography, X-Ray
  • Cyclin D
  • Cyclin-Dependent Kinase 6
  • Cyclin-Dependent Kinase Inhibitor p16 / chemistry*
  • Cyclin-Dependent Kinase Inhibitor p16 / genetics
  • Cyclin-Dependent Kinase Inhibitor p16 / metabolism
  • Cyclin-Dependent Kinase Inhibitor p16 / pharmacology
  • Cyclin-Dependent Kinase Inhibitor p19
  • Cyclin-Dependent Kinases*
  • Cyclins / metabolism
  • Enzyme Inhibitors
  • Escherichia coli
  • Genes, Tumor Suppressor
  • Humans
  • Models, Molecular
  • Molecular Sequence Data
  • Protein Binding
  • Protein Conformation
  • Protein-Serine-Threonine Kinases / antagonists & inhibitors
  • Protein-Serine-Threonine Kinases / chemistry*
  • Protein-Serine-Threonine Kinases / genetics
  • Protein-Serine-Threonine Kinases / metabolism
  • Recombinant Proteins / chemistry
  • Recombinant Proteins / metabolism
  • Structure-Activity Relationship

Substances

  • CDKN2D protein, human
  • Carrier Proteins
  • Cell Cycle Proteins
  • Cyclin D
  • Cyclin-Dependent Kinase Inhibitor p16
  • Cyclin-Dependent Kinase Inhibitor p19
  • Cyclins
  • Enzyme Inhibitors
  • Recombinant Proteins
  • Adenosine Triphosphate
  • Protein-Serine-Threonine Kinases
  • CDK6 protein, human
  • Cyclin-Dependent Kinase 6
  • Cyclin-Dependent Kinases

Associated data

  • PDB/1B17
  • PDB/1B18