1mn9
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NDP kinase mutant (H122G) complex with RTP
OverviewOverview
Ribavirin used in therapies against hepatitis C virus (HCV) is potentially, efficient against other viruses but presents a high cytotoxicity. Several, ribavirin triphosphate analogs modified on the ribose moiety were, synthesized and tested in vitro on the RNA polymerases of HCV, phage T7, and HIV-1 reverse transcriptase. Modified nucleotides with 2'-deoxy, 3'-deoxy, 2',3'-dideoxy, 2',3'-dideoxy-2',3'-dehydro, and, 2',3'-epoxy-ribose inhibited the HCV enzyme but not the other two, polymerases. They were also analyzed as substrates for nucleoside, diphosphate (NDP) kinase, the enzyme responsible for the last step of the, cellular activation of antiviral nucleoside analogs. An X-ray structure of, NDP kinase complexed with ribavirin triphosphate was determined. It, demonstrates that the analog binds as a normal substrate despite the, modified base and confirms the crucial role of the 3'-hydroxyl group in, the phosphorylation reaction. The 3'-hydroxyl is required for inhibition, of the initiation step of RNA synthesis by HCV polymerase, and both sugar, hydroxyls must be present to inhibit elongation. The 2'deoxyribavirin is, the only derivative efficient in vitro against HCV polymerase and properly, activated by NDP kinase.
About this StructureAbout this Structure
1MN9 is a Single protein structure of sequence from Dictyostelium discoideum with MG and RTP as ligands. Active as Nucleoside-diphosphate kinase, with EC number 2.7.4.6 Full crystallographic information is available from OCA.
ReferenceReference
Structural analysis of the activation of ribavirin analogs by NDP kinase: comparison with other ribavirin targets., Gallois-Montbrun S, Chen Y, Dutartre H, Sophys M, Morera S, Guerreiro C, Schneider B, Mulard L, Janin J, Veron M, Deville-Bonne D, Canard B, Mol Pharmacol. 2003 Mar;63(3):538-46. PMID:12606760
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