Crystal structure of the complex of the cyclin D-dependent kinase Cdk6 bound to the cell-cycle inhibitor p19INK4d.
The crystal structure of the cyclin D-dependent kinase Cdk6 bound to the p19 INK4d protein has been determined at 1.9 A resolution. The results provide the first structural information for a cyclin D-dependent protein kinase and show how the INK4 family of CDK inhibitors bind. The structure indicates that the conformational changes induced by p19INK4d inhibit both productive binding of ATP and the cyclin-induced rearrangement of the kinase from an inactive to an active conformation. The structure also shows how binding of an INK4 inhibitor would prevent binding of p27Kip1, resulting in its redistribution to other CDKs. Identification of the critical residues involved in the interaction explains how mutations in Cdk4 and p16INK4a result in loss of kinase inhibition and cancer.
Brotherton
D H
DH
Cambridge Centre for Molecular Recognition, Department of Biochemistry, University of Cambridge, UK.
Dhanaraj
V
V
Wick
S
S
Brizuela
L
L
Domaille
P J
PJ
Volyanik
E
E
Xu
X
X
Parisini
E
E
Smith
B O
BO
Archer
S J
SJ
Serrano
M
M
Brenner
S L
SL
Blundell
T L
TL
Laue
E D
ED
D000255:Adenosine Triphosphate / Q000378:metabolism; D000595:Amino Acid Sequence; D000818:Animals; D001667:Binding, Competitive; D002352:Carrier Proteins / Q000737:chemistry* / Q000378:metabolism; D002384:Catalysis; D018797:Cell Cycle Proteins; D002460:Cell Line; D018360:Crystallography, X-Ray; D051361:Cyclin-Dependent Kinase 6; D019941:Cyclin-Dependent Kinase Inhibitor p16; D050764:Cyclin-Dependent Kinase Inhibitor p19; D018844:Cyclin-Dependent Kinases; D004926:Escherichia coli; D006801:Humans; D007313:Insecta; D051379:Mice; D008969:Molecular Sequence Data; D011487:Protein Conformation; D017346:Protein Serine-Threonine Kinases / Q000737:chemistry* / Q000378:metabolism; D011994:Recombinant Proteins / Q000737:chemistry / Q000378:metabolism; D017386:Sequence Homology, Amino Acid
C493974:CDKN2D protein, human; D002352:Carrier Proteins; C493975:Cdkn2d protein, mouse; D018797:Cell Cycle Proteins; D019941:Cyclin-Dependent Kinase Inhibitor p16; D050764:Cyclin-Dependent Kinase Inhibitor p19; D011994:Recombinant Proteins; D000255:Adenosine Triphosphate; D017346:Protein Serine-Threonine Kinases; C495911:CDK6 protein, human; C495912:Cdk6 protein, mouse; D051361:Cyclin-Dependent Kinase 6; D018844:Cyclin-Dependent Kinases