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
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Adenosine Triphosphate / metabolism
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Amino Acid Sequence
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Binding Sites
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Carrier Proteins / chemistry
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Carrier Proteins / metabolism
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Cell Cycle Proteins*
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Crystallography, X-Ray
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Cyclin D
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Cyclin-Dependent Kinase 6
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Cyclin-Dependent Kinase Inhibitor p16 / chemistry*
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Cyclin-Dependent Kinase Inhibitor p16 / genetics
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Cyclin-Dependent Kinase Inhibitor p16 / metabolism
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Cyclin-Dependent Kinase Inhibitor p16 / pharmacology
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Cyclin-Dependent Kinase Inhibitor p19
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Cyclin-Dependent Kinases*
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Cyclins / metabolism
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Enzyme Inhibitors
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Escherichia coli
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Genes, Tumor Suppressor
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Humans
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Models, Molecular
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Molecular Sequence Data
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Protein Binding
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Protein Conformation
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Protein Serine-Threonine Kinases / antagonists & inhibitors
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Protein Serine-Threonine Kinases / chemistry*
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Protein Serine-Threonine Kinases / genetics
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Protein Serine-Threonine Kinases / metabolism
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Recombinant Proteins / chemistry
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Recombinant Proteins / metabolism
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Structure-Activity Relationship
Substances
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CDKN2D protein, human
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Carrier Proteins
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Cell Cycle Proteins
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Cyclin D
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Cyclin-Dependent Kinase Inhibitor p16
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Cyclin-Dependent Kinase Inhibitor p19
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Cyclins
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Enzyme Inhibitors
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Recombinant Proteins
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Adenosine Triphosphate
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Protein Serine-Threonine Kinases
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CDK6 protein, human
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Cyclin-Dependent Kinase 6
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Cyclin-Dependent Kinases