| Abstract
| - Cyclin-dependent kinases (CDKs) play a central role in cell cycle control, apoptosis, transcription, and neuronal functions. They are important targets for the design of drugs with antimitoticor antineurodegenerative effects. CDK4 and CDK6 form a subfamily among the CDKs inmammalian cells, as defined by sequence similarities. Compared to CDK2 and CDK5, structuralinformation on CDK4 and CDK6 is sparse. We describe here the crystal structure of humanCDK6 in complex with a viral cyclin and a flavonol inhibitor, fisetin. Fisetin binds to the activeform of CDK6, forming hydrogen bonds with the side chains of residues in the binding pocketthat undergo large conformational changes during CDK activation by cyclin binding. The 4-ketogroup and the 3-hydroxyl group of fisetin are hydrogen bonded with the backbone in the hingeregion between the N-terminal and C-terminal kinase domain, as has been observed for manyCDK inhibitors. However, CDK2 and HCK kinase in complex with other flavone inhibitorssuch as quercetin and flavopiridol showed a different binding mode with the inhibitor rotatedby about 180°. The structural information of the CDK6−fisetin complex is correlated with thebinding affinities of different flavone inhibitors for CDK6. This complex structure is the firstdescription of an inhibitor complex with a kinase from the CDK4/6 subfamily and can providea basis for selecting and designing inhibitor compounds with higher affinities and specificities.
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