A structural basis for the inhibition of the NS5 dengue virus mRNA 2'-O-methyltransferase domain by ribavirin 5'-triphosphate.
Ribavirin is one of the few nucleoside analogues currently used in the clinic to treat RNA virus infections, but its mechanism of action remains poorly understood at the molecular level. Here, we show that ribavirin 5'-triphosphate inhibits the activity of the dengue virus 2'-O-methyltransferase NS5 domain (NS5MTase(DV)). Along with several other guanosine 5'-triphosphate analogues such as acyclovir, 5-ethynyl-1-beta-d-ribofuranosylimidazole-4-carboxamide (EICAR), and a series of ribose-modified ribavirin analogues, ribavirin 5'-triphosphate competes with GTP to bind to NS5MTase(DV). A structural view of the binding of ribavirin 5'-triphosphate to this enzyme was obtained by determining the crystal structure of a ternary complex consisting of NS5MTase(DV), ribavirin 5'-triphosphate, and S-adenosyl-l-homocysteine at a resolution of 2.6 A. These detailed atomic interactions provide the first structural insights into the inhibition of a viral enzyme by ribavirin 5'-triphosphate, as well as the basis for rational drug design of antiviral agents with improved specificity against the emerging flaviviruses.
Benarroch
Delphine
D
Centre National de la Recherche Scientifique and Universités d'Aix-Marseille I et II, UMR 6098, Architecture et Fonction des Macromolécules Biologiques, Ecole Supérieur d'Ingénieurs de Luminy-Case 925, 163 avenue de Luminy, 13288 Marseille cedex 9, France.
Egloff
Marie-Pierre
MP
Mulard
Laurence
L
Guerreiro
Catherine
C
Romette
Jean-Louis
JL
Canard
Bruno
B
D001665:Binding Sites; D003715:Dengue / Q000188:drug therapy; D003716:Dengue Virus / Q000201:enzymology; D008780:Methyltransferases / Q000037:antagonists & inhibitors / Q000737:chemistry*; D008958:Models, Molecular; D009711:Nucleotides / Q000737:chemistry* / Q000494:pharmacology; D011485:Protein Binding; D011487:Protein Conformation; D017434:Protein Structure, Tertiary; D014764:Viral Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry
D009711:Nucleotides; D014764:Viral Proteins; C037827:ribavirin 5'-triphosphate; D008780:Methyltransferases; C055099:mRNA (nucleoside-O(2'))-methyltransferase