8CUR

Crystal structure of Cdk2 in complex with Cyclin A inhibitor 6-[(E)-2-(4-chlorophenyl)ethenyl]-2-{[(2R)-3-(4-hydroxyphenyl)-1-methoxy-1-oxopropan-2-yl]carbamoyl}quinoline-4-carboxylic acid

Summary for 8CUR

• Entry DOI: 10.2210/pdb8cur/pdb
• Descriptor: Cyclin-dependent kinase 2, 6-[(E)-2-(4-chlorophenyl)ethenyl]-2-{[(2R)-3-(4-hydroxyphenyl)-1-methoxy-1-oxopropan-2-yl]carbamoyl}quinoline-4-carboxylic acid (3 entities in total)
• Functional Keywords: cell cycle, protein-inhibitor complex, kinase, transferase-inhibitor complex, transferase/inhibitor
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 1
• Total formula weight: 34507.44

Authors

Tripathi, S.M.,Tambo, C.S.,Kiss, G.,Rubin, S.M. (deposition date: 2022-05-17, release date: 2023-04-05, Last modification date: 2023-10-25)

Primary citation

Tambo, C.S.,Tripathi, S.,Perera, B.G.K.,Maly, D.J.,Bridges, A.J.,Kiss, G.,Rubin, S.M.
Biolayer Interferometry Assay for Cyclin-Dependent Kinase-Cyclin Association Reveals Diverse Effects of Cdk2 Inhibitors on Cyclin Binding Kinetics.
Acs Chem.Biol., 18:431-440, 2023

PubMed Abstract: Cyclin-dependent kinases (CDKs) are key mediators of cell proliferation and have been a subject of oncology drug discovery efforts for over two decades. Several CDK and activator cyclin family members have been implicated in regulating the cell division cycle. While it is thought that there are canonical CDK-cyclin pairing preferences, the extent of selectivity is unclear, and increasing evidence suggests that the cell-cycle CDKs can be activated by a pool of available cyclins. The molecular details of CDK-cyclin specificity are not completely understood despite their importance for understanding cancer cell cycles and for pharmacological inhibition of cancer proliferation. We report here a biolayer interferometry assay that allows for facile quantification of CDK binding interactions with their cyclin activators. We applied this assay to measure the impact of Cdk2 inhibitors on Cyclin A (CycA) association and dissociation kinetics. We found that Type I inhibitors increase the affinity between Cdk2 and CycA by virtue of a slowed cyclin dissociation rate. In contrast, Type II inhibitors and other small-molecule Cdk2 binders have distinct effects on the CycA association and dissociation processes to decrease affinity. We propose that the differential impact of small molecules on the cyclin binding kinetics arises from the plasticity of the Cdk2 active site as the kinase transitions between active, intermediate, and inactive states.

PubMed: 36724382
DOI: 10.1021/acschembio.3c00015

Experimental method

X-RAY DIFFRACTION (2.2 Å)