5cr7

Human cytosolic 5'-nucleotidase II in complex with N-(9H-Purin-6-yl)-3-(3-pyrrol-1-ylphenyl)benzamide

spinqualitylabelsall models 5cr7, resolution 2.90Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 5cr7 is a 2 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 2.9Å Ligands: 5WO, ACT, GOL, MG, PO4 Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Disease 5NTC_HUMAN Autosomal recessive spastic paraplegia type 45. The disease is caused by mutations affecting the gene represented in this entry. Function 5NTC_HUMAN May have a critical role in the maintenance of a constant composition of intracellular purine/pyrimidine nucleotides in cooperation with other nucleotidases. Preferentially hydrolyzes inosine 5'-monophosphate (IMP) and other purine nucleotides. Publication Abstract from PubMed We used a combined approach based on fragment-based drug design (FBDD) and in silico methods to design potential inhibitors of the cytosolic 5'-nucleotidase II (cN-II), which has been recognized as an important therapeutic target in hematological cancers. Two subgroups of small compounds (including adenine and biaryl moieties) were identified as cN-II binders and a fragment growing strategy guided by molecular docking was considered. Five compounds induced a strong inhibition of the 5'-nucleotidase activity in vitro, and the most potent ones were characterized as noncompetitive inhibitors. Biological evaluation in cancer cell lines showed synergic effect with selected anticancer drugs. Structural studies using X-ray crystallography lead to the identification of new binding sites for two derivatives and of a new crystal form showing important domain swapping. Altogether, the strategy developed herein allowed identifying new original noncompetitive inhibitors against cN-II that act in a synergistic manner with well-known antitumoral agents. Identification of Noncompetitive Inhibitors of Cytosolic 5'-Nucleotidase II Using a Fragment-Based Approach.,Marton Z, Guillon R, Krimm I, Preeti, Rahimova R, Egron D, Jordheim LP, Aghajari N, Dumontet C, Perigaud C, Lionne C, Peyrottes S, Chaloin L J Med Chem. 2015 Dec 24;58(24):9680-96. doi: 10.1021/acs.jmedchem.5b01616. Epub, 2015 Dec 7. PMID:26599519 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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