Structure of the cyclin-dependent kinase inhibitor p19Ink4d.
In cancer, the biochemical pathways that are dominated by the two tumour-suppressor proteins, p53 and Rb, are the most frequently disrupted. Cyclin D-dependent kinases phosphorylate Rb to control its activity and they are, in turn, specifically inhibited by the Ink4 family of cyclin-dependent kinase inhibitors (CDKIs) which cause arrest at the G1 phase of the cell cycle. Mutations in Rb, cyclin D1, its catalytic subunit Cdk4, and the CDKI p16Ink4a, which alter the protein or its level of expression, are all strongly implicated in cancer. This suggests that the Rb 'pathway' is of particular importance. Here we report the structure of the p19Ink4d protein, determined by NMR spectroscopy. The structure indicates that most mutations to the p16Ink4a gene, which result in loss of function, are due to incorrectly folded and/or insoluble proteins. We propose a model for the interaction of Ink4 proteins with D-type cyclin-Cdk4/6 complexes that might provide a basis for the design of therapeutics against cancer. The sequences of the Ink4 family of CDKIs are highly conserved
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Cambridge Centre for Molecular Recognition, Department of Biochemistry, University of Cambridge, UK.
Archer
S J
SJ
Domaille
P J
PJ
Smith
B O
BO
Owen
D
D
Brotherton
D H
DH
Raine
A R
AR
Xu
X
X
Brizuela
L
L
Brenner
S L
SL
Laue
E D
ED
D000595:Amino Acid Sequence; D000818:Animals; D017487:Ankyrins / Q000737:chemistry; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology; D002352:Carrier Proteins / Q000737:chemistry* / Q000235:genetics / Q000494:pharmacology; D018797:Cell Cycle Proteins; D056741:Cyclin D; D051358:Cyclin-Dependent Kinase 4; D019941:Cyclin-Dependent Kinase Inhibitor p16; D050764:Cyclin-Dependent Kinase Inhibitor p19; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors*; D016213:Cyclins / Q000187:drug effects; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D051379:Mice; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009154:Mutation; D011487:Protein Conformation; D011518:Proto-Oncogene Proteins; D011993:Recombinant Fusion Proteins / Q000737:chemistry / Q000235:genetics; D017386:Sequence Homology, Amino Acid
D017487:Ankyrins; D000970:Antineoplastic Agents; C493974:CDKN2D protein, human; D002352:Carrier Proteins; C493975:Cdkn2d protein, mouse; D018797:Cell Cycle Proteins; D056741:Cyclin D; D019941:Cyclin-Dependent Kinase Inhibitor p16; D050764:Cyclin-Dependent Kinase Inhibitor p19; D016213:Cyclins; D004791:Enzyme Inhibitors; D011518:Proto-Oncogene Proteins; D011993:Recombinant Fusion Proteins; C495900:CDK4 protein, human; C495902:Cdk4 protein, mouse; D051358:Cyclin-Dependent Kinase 4; D018844:Cyclin-Dependent Kinases