2C5Y: Differential Binding Of Inhibitors To Active And Inactive Cdk2 Provides Insights For Drug Design

Citation:
Abstract
The cyclin-dependent kinases (CDKs) have been characterized in complex with a variety of inhibitors, but the majority of structures solved are in the inactive form. We have solved the structures of six inhibitors in both the monomeric CDK2 and binary CDK2/cyclinA complexes and demonstrate that significant differences in ligand binding occur depending on the activation state. The binding mode of two ligands in particular varies substantially in active and inactive CDK2. Furthermore, energetic analysis of CDK2/cyclin/inhibitors demonstrates that a good correlation exists between the in vitro potency and the calculated energies of interaction, but no such relationship exists for CDK2/inhibitor structures. These results confirm that monomeric CDK2 ligand complexes do not fully reflect active conformations, revealing significant implications for inhibitor design while also suggesting that the monomeric CDK2 conformation can be selectively inhibited.
PDB ID: 2C5YDownload
MMDB ID: 38082
PDB Deposition Date: 2005/11/3
Updated in MMDB: 2007/10
Experimental Method:
x-ray diffraction
Resolution: 2.25  Å
Source Organism:
Similar Structures:
Biological Unit for 2C5Y: monomeric; determined by author and by software (PQS)
Molecular Components in 2C5Y
Label Count Molecule
Protein (1 molecule)
1
Cell Division Protein Kinase 2(Gene symbol: CDK2)
Molecule annotation
Chemical (1 molecule)
1
1
* Click molecule labels to explore molecular sequence information.

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