Related Experiment Video
Updated: Feb 8, 2026
Kinase Inhibitor Screening In Self-assembled Human Protein Microarrays
Published on: October 23, 2019
Crystal structure of a human cyclin-dependent kinase 6 complex with a flavonol inhibitor, fisetin
Heshu Lu1, Debbie J Chang, Blandine Baratte
1Physical Biosciences Division, Lawrence Berkeley National Laboratory, 1 Cyclotron Road, MS 64R0121, Berkeley, California 94720, USA.
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 antimitotic or antineurodegenerative effects. CDK4 and CDK6 form a subfamily among the CDKs in mammalian cells, as defined by sequence similarities. Compared to CDK2 and CDK5, structural information on CDK4 and CDK6 is sparse. We describe here the crystal structure of human CDK6 in complex with a viral cyclin and a flavonol inhibitor, fisetin. Fisetin binds to the active form of CDK6, forming hydrogen bonds with the side chains of residues in the binding pocket that undergo large conformational changes during CDK activation by cyclin binding. The 4-keto group and the 3-hydroxyl group of fisetin are hydrogen bonded with the backbone in the hinge region between the N-terminal and C-terminal kinase domain, as has been observed for many CDK inhibitors. However, CDK2 and HCK kinase in complex with other flavone inhibitors such as quercetin and flavopiridol showed a different binding mode with the inhibitor rotated by about 180 degrees. The structural information of the CDK6-fisetin complex is correlated with the binding affinities of different flavone inhibitors for CDK6. This complex structure is the first description of an inhibitor complex with a kinase from the CDK4/6 subfamily and can provide a basis for selecting and designing inhibitor compounds with higher affinities and specificities.
Insights
We determined the crystal structure of human cyclin-dependent kinase 6 (CDK6) complexed with fisetin. This reveals how fisetin binds to CDK6, offering insights for developing targeted cancer and neurodegenerative disease therapies.
Area of Science:
- Biochemistry
- Structural Biology
- Pharmacology
Background:
- Cyclin-dependent kinases (CDKs) are crucial regulators of cell cycle, apoptosis, and transcription.
- CDK4 and CDK6 form a distinct subfamily within CDKs, implicated in cell cycle control.
- Limited structural data exists for CDK4/6 subfamily kinases compared to CDK2 and CDK5.
Purpose of the Study:
- To elucidate the structural basis of inhibitor binding to CDK6.
- To provide a foundation for designing novel CDK4/6 inhibitors with enhanced affinity and specificity.
- To understand the interaction of flavonol inhibitors with the CDK4/6 kinase family.
Main Methods:
- X-ray crystallography was employed to determine the structure of human CDK6.
- The structure was solved in complex with a viral cyclin and the flavonol inhibitor fisetin.
- Binding affinities of various flavone inhibitors to CDK6 were correlated with the structural data.
Main Results:
- The crystal structure of human CDK6 in complex with a viral cyclin and fisetin was determined.
- Fisetin binds to the active conformation of CDK6, forming key hydrogen bonds within the kinase domain.
- The binding mode of fisetin differs from other flavone inhibitors observed in CDK2 and HCK kinases.
Conclusions:
- This study presents the first inhibitor complex structure for the CDK4/6 subfamily.
- The CDK6-fisetin structure provides critical insights into inhibitor interactions and guides the design of selective CDK4/6 modulators.
- Understanding these interactions can advance therapeutic strategies targeting cell proliferation and neurodegeneration.
Related Concept Videos
02:58Crystal Field Theory - Octahedral Complexes
To explain the observed behavior of transition metal complexes (such as colors), a model involving electrostatic interactions between the electrons from the ligands and the electrons in the unhybridized d orbitals of the central metal atom has been developed. This electrostatic model is crystal field theory (CFT). It helps to understand, interpret, and predict the colors, magnetic behavior, and some structures of coordination compounds of transition metals.
CFT focuses on...
02:42Ionic Crystal Structures
Most monatomic ions behave as charged spheres, and their attraction for ions of opposite charge is the same in every direction. Consequently, stable structures for ionic compounds result (1) when ions of one charge are surrounded by as many ions as possible of the opposite...
02:46Crystal Field Theory - Tetrahedral and Square Planar Complexes
Crystal field theory (CFT) is applicable to molecules in geometries other than octahedral. In octahedral complexes, the lobes of the dx2−y2 and dz2 orbitals point directly at the ligands. For tetrahedral complexes, the d orbitals remain in place, but with only four ligands located between the axes. None of the orbitals points directly at the tetrahedral ligands. However, the dx2−y2 and dz2 orbitals (along the Cartesian axes) overlap with the ligands less than the dxy,...
01:25cAMP-dependent Protein Kinase Pathways
02:54Protein Kinases and Phosphatases
Protein kinases
Many proteins in the cell are regulated by phosphorylation, the addition of a phosphate group. A family of enzymes called kinases...
01:32Assembly of Complex Microtubule Structures