4WH9

Structure of the CDC25B Phosphatase Catalytic Domain with Bound Inhibitor

Summary for 4WH9

• Entry DOI: 10.2210/pdb4wh9/pdb
• Related: 4WH7
• Descriptor: M-phase inducer phosphatase 2, 2-[(2-cyano-3-fluoro-5-hydroxyphenyl)sulfanyl]ethanesulfonic acid, SULFATE ION, ... (5 entities in total)
• Functional Keywords: phosphatase, inhibitor, fragment, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 1
• Total formula weight: 22203.06

Authors

Lund, G.L.,Dudkin, S.,Borkin, D.,Ni, W.,Grembecka, J.,Cierpicki, T. (deposition date: 2014-09-20, release date: 2014-12-10, Last modification date: 2023-09-27)

Primary citation

Lund, G.,Dudkin, S.,Borkin, D.,Ni, W.,Grembecka, J.,Cierpicki, T.
Inhibition of CDC25B Phosphatase Through Disruption of Protein-Protein Interaction.
Acs Chem.Biol., 10:390-394, 2015

PubMed Abstract: CDC25 phosphatases are key cell cycle regulators and represent very attractive but challenging targets for anticancer drug discovery. Here, we explored whether fragment-based screening represents a valid approach to identify inhibitors of CDC25B. This resulted in identification of 2-fluoro-4-hydroxybenzonitrile, which directly binds to the catalytic domain of CDC25B. Interestingly, NMR data and the crystal structure demonstrate that this compound binds to the pocket distant from the active site and adjacent to the protein-protein interaction interface with CDK2/Cyclin A substrate. Furthermore, we developed a more potent analogue that disrupts CDC25B interaction with CDK2/Cyclin A and inhibits dephosphorylation of CDK2. Based on these studies, we provide a proof of concept that targeting CDC25 phosphatases by inhibiting their protein-protein interactions with CDK2/Cyclin A substrate represents a novel, viable opportunity to target this important class of enzymes.

PubMed: 25423142
DOI: 10.1021/cb500883h

Experimental method

X-RAY DIFFRACTION (1.5 Å)