1mn9: Difference between revisions

Revision as of 01:27, 3 May 2008

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. 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 Page seeded by OCA on Sat May 3 01:26:59 2008

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OCA

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 [[Image:1mn9.gif|left|200px]]
- {{Structure
+<!--
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+The line below this paragraph, containing "STRUCTURE_1mn9", creates the "Structure Box" on the page.
-|SITE=
+You may change the PDB parameter (which sets the PDB file loaded into the applet)
-|LIGAND= <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene>, <scene name='pdbligand=RTP:RIBAVIRIN+TRIPHOSPHATE'>RTP</scene>
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-|ACTIVITY= <span class='plainlinks'>[http://en.wikipedia.org/wiki/Nucleoside-diphosphate_kinase Nucleoside-diphosphate kinase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.4.6 2.7.4.6] </span>
+or leave the SCENE parameter empty for the default display.
-|GENE=
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-|DOMAIN=
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-|RELATEDENTRY=[[1f3f|1f3f]], [[1nue|1nue]]
-|RESOURCES=<span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=1mn9 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1mn9 OCA], [http://www.ebi.ac.uk/pdbsum/1mn9 PDBsum], [http://www.rcsb.org/pdb/explore.do?structureId=1mn9 RCSB]</span>
-}}
 '''NDP kinase mutant (H122G) complex with RTP'''
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 [[Category: Schneider, B.]]
 [[Category: Veron, M.]]
-[[Category: ndp kinase-ribavirin complex]]
+[[Category: Ndp kinase-ribavirin complex]]
+''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Sat May  3 01:26:59 2008''
-''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Sun Mar 30 22:18:28 2008''