1q92

Crystal structure of human mitochondrial deoxyribonucleotidase in complex with the inhibitor PMcP-U

spinqualitylabelsall models 1q92, resolution 1.40Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 1q92 is a 1 chain structure with sequence from Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Ligands: DRM, GOL, MG Related: 1mh9, 1q91 Activity: 5'-nucleotidase, with EC number 3.1.3.5 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. Evolutionary Conservation Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf. Publication Abstract from PubMed Monophosphate nucleotidases are enzymes that dephosphorylate nucleotides to their corresponding nucleosides. They play potentially important roles in controlling the activation of nucleotide-based drugs targeted against viral infections or cancer cells. The human mitochondrial deoxyribonucleotidase (dNT-2) dephosphorylates thymidine and deoxyuridine monophosphates. We describe the high resolution structures of the dNT-2 enzyme in complex with two potent nucleoside phosphonate inhibitors, (S)-1-[2'-deoxy-3',5'-O-(1-phosphono) benzylidene-beta-d-threo-pentofuranosyl]thymine (DPB-T) at 1.6-A resolution and (+/-)-1-trans-(2-phosphonomethoxycyclopentyl)uracil (PMcP-U) at 1.4-A resolution. The mixed competitive inhibitor DPB-T and the competitive inhibitor PMcP-U both bind in the active site of dNT-2 but in distinctly different binding modes, explaining their different kinetics of inhibition. The pyrimidine part of the inhibitors binds with very similar hydrogen bond interactions to the protein but with their phosphonate moieties in different binding sites compared with each other and to the previously determined position of phosphate bound to dNT-2. Together, these phosphate/phosphonate binding sites describe what might constitute a functionally relevant phosphate entrance tunnel to the active site. The structures of the inhibitors in complex with dNT-2, being the first such complexes of any nucleotidase, might provide important information for the design of more specific inhibitors to control the activation of nucleotide-based drugs. Crystal structures of the mitochondrial deoxyribonucleotidase in complex with two specific inhibitors.,Rinaldo-Matthis A, Rampazzo C, Balzarini J, Reichard P, Bianchi V, Nordlund P Mol Pharmacol. 2004 Apr;65(4):860-7. PMID:15044615 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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