8c25

purine nucleoside phosphorylase in complex with JS-375

spinqualitylabelsall models 8c25, resolution 1.56Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 8c25 is a 2 chain structure with sequence from Mycobacterium tuberculosis. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 1.56Å Ligands: CL, GOL, JU9, NA Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function A0A045IAS2_MYCTX The purine nucleoside phosphorylases catalyze the phosphorolytic breakdown of the N-glycosidic bond in the beta-(deoxy)ribonucleoside molecules, with the formation of the corresponding free purine bases and pentose-1-phosphate. Cleaves guanosine, inosine, 2'-deoxyguanosine and 2'-deoxyinosine.[ARBA:ARBA00002678] Publication Abstract from PubMed Purine nucleoside phosphorylase (PNP) is a well-known molecular target with potential therapeutic applications in the treatment of T-cell malignancies and/or bacterial/parasitic infections. Here, we report the design, development of synthetic methodology, and biological evaluation of a series of 30 novel PNP inhibitors based on acyclic nucleoside phosphonates bearing a 9-deazahypoxanthine nucleobase. The strongest inhibitors exhibited IC(50) values as low as 19 nM (human PNP) and 4 nM (Mycobacterium tuberculosis (Mt) PNP) and highly selective cytotoxicity toward various T-lymphoblastic cell lines with CC(50) values as low as 9 nM. No cytotoxic effect was observed on other cancer cell lines (HeLa S3, HL60, HepG2) or primary PBMCs for up to 10 muM. We report the first example of the PNP inhibitor exhibiting over 60-fold selectivity for the pathogenic enzyme (MtPNP) over hPNP. The results are supported by a crystallographic study of eight enzyme-inhibitor complexes and by ADMET profiling in vitro and in vivo. Design, Synthesis, Biological Evaluation, and Crystallographic Study of Novel Purine Nucleoside Phosphorylase Inhibitors.,Skacel J, Djukic S, Baszczynski O, Kalcic F, Bilek T, Chalupsky K, Kozak J, Dvorakova A, Tloust'ova E, Kral'ova Z, Smidkova M, Voldrich J, Rumlova M, Pachl P, Brynda J, Vuckova T, Fabry M, Snasel J, Pichova I, Rezacova P, Mertlikova-Kaiserova H, Janeba Z J Med Chem. 2023 May 25;66(10):6652-6681. doi: 10.1021/acs.jmedchem.2c02097. Epub , 2023 May 3. PMID:37134237 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Purine nucleoside phosphorylase 3D structures

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