5AES

Crystal Structure of murine Chronophin (Pyridoxal Phosphate Phosphatase) in Complex with a PNP-derived Inhibitor

Summary for 5AES

• Entry DOI: 10.2210/pdb5aes/pdb
• Descriptor: PYRIDOXAL PHOSPHATE PHOSPHATASE, MAGNESIUM ION, {2-[5-hydroxy-4-(hydroxymethyl)-6-methylpyridin-3-yl]ethyl}phosphonic acid, ... (5 entities in total)
• Functional Keywords: hydrolase, pdxp, plpp, haloacid dehalogenase, had phosphatase, had hydrolase
• Biological source: MUS MUSCULUS (HOUSE MOUSE)
• Cellular location: Cytoplasm, cytosol : P60487
• Total number of polymer chains: 2
• Total formula weight: 63864.93

Authors

Knobloch, G.,Jabari, N.,Koehn, M.,Gohla, A.,Schindelin, H. (deposition date: 2015-01-09, release date: 2015-04-01, Last modification date: 2024-10-23)

Primary citation

Knobloch, G.,Jabari, N.,Stadlbauer, S.,Schindelin, H.,Kohn, M.,Gohla, A.
Synthesis of Hydrolysis-Resistant Pyridoxal 5'-Phosphate Analogs and Their Biochemical and X-Ray Crystallographic Characterization with the Pyridoxal Phosphatase Chronophin.
Bioorg.Med.Chem., 23:2819-, 2015

PubMed Abstract: A 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 79μM, 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 2.75Å 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.

PubMed: 25783190
DOI: 10.1016/J.BMC.2015.02.049

Experimental method

X-RAY DIFFRACTION (2.751 Å)