4wh9

Structure of the CDC25B Phosphatase Catalytic Domain with Bound Inhibitor

spinqualitylabelsall models 4wh9, resolution 1.50Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 4wh9 is a 1 chain structure with sequence from Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Ligands: 3M8, GOL, SO4 Related: 4wh7 Gene: CDC25B, CDC25HU2 (HUMAN) Activity: Protein-tyrosine-phosphatase, with EC number 3.1.3.48 Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function [MPIP2_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. Publication Abstract from PubMed 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. 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 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Tyrosine phosphatase

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