4EOO: Thr 160 Phosphorylated Cdk2 Q131e - Human Cyclin A3 Complex With Atp

Cdk2 promotes DNA replication and is a promising cancer therapeutic target, but its functions appear redundant with Cdk1, an essential Cdk affected by most Cdk2 inhibitors. Here, we present an integrated multidisciplinary approach to address Cdk redundancy. Mathematical modeling of enzymology data predicted conditions allowing selective chemical Cdk2 inhibition. Together with experiments in Xenopus egg extracts, this supports a rate-limiting role for Cdk2 in DNA replication. To confirm this we designed inhibitor-resistant (ir)-Cdk2 mutants using a novel bioinformatics approach. Bypassing inhibition with ir-Cdk2 or with Cdk1 shows that Cdk2 is rate-limiting for replication in this system because Cdk1 is insufficiently active. Additionally, crystal structures and kinetics reveal alternative binding modes of Cdk1-selective and Cdk2-selective inhibitors and mechanisms of Cdk2 inhibitor resistance. Our approach thus provides insight into structure, functions, and biochemistry of a cyclin-dependent kinase.
PDB ID: 4EOODownload
MMDB ID: 107308
PDB Deposition Date: 2012/4/14
Updated in MMDB: 2013/02
Experimental Method:
x-ray diffraction
Resolution: 2.1  Å
Source Organism:
Similar Structures:
Biological Unit for 4EOO: dimeric; determined by author and by software (PISA)
Molecular Components in 4EOO
Label Count Molecule
Proteins (2 molecules)
Cyclin-dependent Kinase 2(Gene symbol: CDK2)
Molecule annotation
Cyclin-a2(Gene symbol: CCNA2)
Molecule annotation
Chemicals (4 molecules)
* Click molecule labels to explore molecular sequence information.

Citing MMDB