Crystal structure of human CDK4 in complex with a D-type cyclin.
The cyclin D1-cyclin-dependent kinase 4 (CDK4) complex is a key regulator of the transition through the G(1) phase of the cell cycle. Among the cyclin/CDKs, CDK4 and cyclin D1 are the most frequently activated by somatic genetic alterations in multiple tumor types. Thus, aberrant regulation of the CDK4/cyclin D1 pathway plays an essential role in oncogenesis; hence, CDK4 is a genetically validated therapeutic target. Although X-ray crystallographic structures have been determined for various CDK/cyclin complexes, CDK4/cyclin D1 has remained highly refractory to structure determination. Here, we report the crystal structure of CDK4 in complex with cyclin D1 at a resolution of 2.3 A. Although CDK4 is bound to cyclin D1 and has a phosphorylated T-loop, CDK4 is in an inactive conformation and the conformation of the heterodimer diverges from the previously known CDK/cyclin binary complexes, which suggests a unique mechanism for the process of CDK4 regulation and activation.
Day
Philip J
PJ
Astex Therapeutics Ltd., 436 Cambridge Science Park, Milton Road, Cambridge CB4 0QA, United Kingdom.
Cleasby
Anne
A
Tickle
Ian J
IJ
O'Reilly
Marc
M
Coyle
Joe E
JE
Holding
Finn P
FP
McMenamin
Rachel L
RL
Yon
Jeff
J
Chopra
Rajiv
R
Lengauer
Christoph
C
Jhoti
Harren
H
D018360:Crystallography, X-Ray; D019938:Cyclin D1 / Q000737:chemistry*; D051358:Cyclin-Dependent Kinase 4 / Q000737:chemistry*; D006801:Humans; D046912:Multiprotein Complexes / Q000737:chemistry; D011485:Protein Binding; D011487:Protein Conformation
D046912:Multiprotein Complexes; D019938:Cyclin D1; C495900:CDK4 protein, human; D051358:Cyclin-Dependent Kinase 4