5aes
From Proteopedia
Crystal Structure of murine Chronophin (Pyridoxal Phosphate Phosphatase) in Complex with a PNP-derived Inhibitor
Structural highlights
FunctionPLPP_MOUSE Protein serine phosphatase that dephosphorylates 'Ser-3' in cofilin and probably also dephosphorylates phospho-serine residues in DSTN. Regulates cofilin-dependent actin cytoskeleton reorganization. Required for normal progress through mitosis and normal cytokinesis. Does not dephosphorylate phospho-threonines in LIMK1. Does not dephosphorylate peptides containing phospho-tyrosine. Pyridoxal phosphate phosphatase. Has some activity towards pyridoxal 5'-phosphate (PLP), pyridoxine 5'-phosphate (PMP) and pyridoxine 5'-phosphate (PNP), with a highest activity with PLP followed by PNP (By similarity). Publication Abstract from PubMedA set of phosphonic acid derivatives (1-4) of pyridoxal 5'-phosphate (PLP) was synthesized and characterized biochemically using purified murine pyridoxal phosphatase (PDXP), also known as chronophin. The most promising compound 1 displayed primarily competitive PDXP inhibitory activity with an IC50 value of 79muM, which was in the range of the Km of the physiological substrate PLP. We also report the X-ray crystal structure of PDXP bound to compound 3, which we solved to 2.75A resolution (PDB code 5AES). The co-crystal structure proves that compound 3 binds in the same orientation as PLP, and confirms the mode of inhibition to be competitive. Thus, we identify compound 1 as a PDXP phosphatase inhibitor. Our results suggest a strategy to design new, potent and selective PDXP inhibitors, which may be useful to increase the sensitivity of tumor cells to treatment with cytotoxic agents. Synthesis of hydrolysis-resistant pyridoxal 5'-phosphate analogs and their biochemical and X-ray crystallographic characterization with the pyridoxal phosphatase chronophin.,Knobloch G, Jabari N, Stadlbauer S, Schindelin H, Kohn M, Gohla A Bioorg Med Chem. 2015 Mar 4. pii: S0968-0896(15)00153-4. doi:, 10.1016/j.bmc.2015.02.049. PMID:25783190[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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