1q92
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(New page: 200px<br /> <applet load="1q92" size="450" color="white" frame="true" align="right" spinBox="true" caption="1q92, resolution 1.40Å" /> '''Crystal structure o...)
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Revision as of 16:45, 12 November 2007
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Crystal structure of human mitochondrial deoxyribonucleotidase in complex with the inhibitor PMcP-U
Overview
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.
About this Structure
1Q92 is a Single protein structure of sequence from Homo sapiens with MG, DRM and GOL as ligands. Active as 5'-nucleotidase, with EC number 3.1.3.5 Full crystallographic information is available from OCA.
Reference
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
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