4wh9
From Proteopedia
Structure of the CDC25B Phosphatase Catalytic Domain with Bound Inhibitor
Structural highlights
FunctionMPIP2_HUMAN Tyrosine protein phosphatase which functions as a dosage-dependent inducer of mitotic progression. Required for G2/M phases of the cell cycle progression and abscission during cytokinesis in a ECT2-dependent manner. Directly dephosphorylates CDK1 and stimulates its kinase activity. The three isoforms seem to have a different level of activity.[1] Publication Abstract from PubMedCDC25 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. Inhibition of CDC25B Phosphatase Through Disruption of Protein-Protein Interaction.,Lund G, Dudkin S, Borkin D, Ni W, Grembecka J, Cierpicki T ACS Chem Biol. 2014 Dec 1. PMID:25423142[2] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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Categories: Homo sapiens | Large Structures | Borkin D | Cierpicki T | Dudkin S | Grembecka J | Lund GL | Ni W
