A structural basis for the inhibition of the NS5 dengue virus mRNA 2′-O-Methyltransferase domain by ribavirin 5′-triphosphate

被引:137
作者
Benarroch, D
Egloff, MP
Mulard, L
Guerreiro, C
Romette, JL
Canard, B
机构
[1] CNRS, F-13288 Marseille 9, France
[2] Univ Aix Marseille 1, UMR 6098, Ecole Super Ingenieurs Luminy, F-13288 Marseille 9, France
[3] Univ Aix Marseille 2, UMR 6098, Ecole Super Ingenieurs Luminy, F-13288 Marseille 9, France
[4] Inst Pasteur, Unite Chim Organ, F-75724 Paris 15, France
关键词
D O I
10.1074/jbc.M400460200
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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 NS5MTaseDV. 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 NS5MTaseDV, ribavirin 5'-triphosphate, and S-adenosyl-L-homocysteine at a resolution of 2.6 Angstrom. 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.
引用
收藏
页码:35638 / 35643
页数:6
相关论文
共 25 条
[1]   Isolation of West Nile virus from mosquitoes, crows, and a Cooper's hawk in Connecticut [J].
Anderson, JF ;
Andreadis, TG ;
Vossbrinck, CR ;
Tirrell, S ;
Wakem, EM ;
French, RA ;
Garmendia, AE ;
Van Kruiningen, HJ .
SCIENCE, 1999, 286 (5448) :2331-2333
[2]   THE CCP4 SUITE - PROGRAMS FOR PROTEIN CRYSTALLOGRAPHY [J].
BAILEY, S .
ACTA CRYSTALLOGRAPHICA SECTION D-BIOLOGICAL CRYSTALLOGRAPHY, 1994, 50 :760-763
[3]  
BALZARINI J, 1993, J BIOL CHEM, V268, P24591
[4]   Viral and cellular enzymes involved in synthesis of mRNA cap structure [J].
Bisaillon, M ;
Lemay, G .
VIROLOGY, 1997, 236 (01) :1-7
[5]   FREE R-VALUE - A NOVEL STATISTICAL QUANTITY FOR ASSESSING THE ACCURACY OF CRYSTAL-STRUCTURES [J].
BRUNGER, AT .
NATURE, 1992, 355 (6359) :472-475
[6]  
Brunger AT, 1998, ACTA CRYSTALLOGR D, V54, P905, DOI 10.1107/s0907444998003254
[7]   FLAVIVIRUS GENOME ORGANIZATION, EXPRESSION, AND REPLICATION [J].
CHAMBERS, TJ ;
HAHN, CS ;
GALLER, R ;
RICE, CM .
ANNUAL REVIEW OF MICROBIOLOGY, 1990, 44 :649-688
[8]   Interferon, ribavirin, 6-azauridine and glycyrrhizin: antiviral compounds active against pathogenic flaviviruses [J].
Crance, JM ;
Scaramozzino, N ;
Jouan, A ;
Garin, D .
ANTIVIRAL RESEARCH, 2003, 58 (01) :73-79
[9]   The broad-spectrum antiviral ribonucleoside ribavirin is an RNA virus mutagen [J].
Crotty, S ;
Maag, D ;
Arnold, JJ ;
Zhong, WD ;
Lau, JYN ;
Hong, Z ;
Andino, R ;
Cameron, CE .
NATURE MEDICINE, 2000, 6 (12) :1375-1379
[10]   An RNA cap (nucleoside-2′-O-)-methyltransferase in the flavivirus RNA polymerase NS5:: crystal structure and functional characterization [J].
Egloff, MP ;
Benarroch, D ;
Selisko, B ;
Romette, JL ;
Canard, B .
EMBO JOURNAL, 2002, 21 (11) :2757-2768