4mwo

Crystal structure of human mitochondrial 5'(3')-deoxyribonucleotidase in complex with the inhibitor CPB-T

spinqualitylabelsall models 4mwo, resolution 1.67Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 4mwo is a 1 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 1.67Å Ligands: 2E2, GOL, K, PO4 Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function NT5M_HUMAN Dephosphorylates specifically the 5' and 2'(3')-phosphates of uracil and thymine deoxyribonucleotides, and so protects mitochondrial DNA replication from excess dTTP. Has only marginal activity towards dIMP and dGMP. Publication Abstract from PubMed This work describes novel in vitro inhibitors of human mitochondrial (mdN) and cytosolic (cdN) 5'(3')-deoxynucleotidases. We designed a series of derivatives of the lead compound (S)-1-[2-deoxy-3,5-O-(phosphonobenzylidene)-beta-d-threo-pentofuranosyl]thymine bearing various substituents in the para position of the benzylidene moiety. Detailed kinetic study revealed that certain para substituents increase the inhibitory potency (iodo derivative; K = 2.71 muM) and some induce a shift in selectivity toward cdN (carboxy derivative, K = 11.60 muM; iodoxy derivative, K = 6.60 muM). Crystal structures of mdN in complex with three of these compounds revealed that various para substituents lead to two alternative inhibitor binding modes within the enzyme active site. Two binding modes were also identified for cdN complexes by heteronuclear NMR spectroscopy. Conformationally constrained nucleoside phosphonic acids - potent inhibitors of human mitochondrial and cytosolic 5'(3')-nucleotidases.,Simak O, Pachl P, Fabry M, Budesinsky M, Jandusik T, Hnizda A, Sklenickova R, Petrova M, Veverka V, Rezacova P, Brynda J, Rosenberg I Org Biomol Chem. 2014 Sep 1. PMID:25178098 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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