Structural and Functional Analyses of a Conserved Hydrophobic Pocket of Flavivirus Methyltransferase
Journal Article
·
· Journal of Biological Chemistry
OSTI ID:1041738
The flavivirus methyltransferase (MTase) sequentially methylates the N7 and 2'-O positions of the viral RNA cap (GpppA-RNA {yields} m(7)GpppA-RNA {yields} m(7)GpppAm-RNA), using S-adenosyl-l-methionine (AdoMet) as a methyl donor. We report here that sinefungin (SIN), an AdoMet analog, inhibits several flaviviruses through suppression of viral MTase. The crystal structure of West Nile virus MTase in complex with SIN inhibitor at 2.0-{angstrom} resolution revealed a flavivirus-conserved hydrophobic pocket located next to the AdoMet-binding site. The pocket is functionally critical in the viral replication and cap methylations. In addition, the N7 methylation efficiency was found to correlate with the viral replication ability. Thus, SIN analogs with modifications that interact with the hydrophobic pocket are potential specific inhibitors of flavivirus MTase.
- Research Organization:
- BROOKHAVEN NATIONAL LABORATORY (BNL)
- Sponsoring Organization:
- USDOE SC OFFICE OF SCIENCE (SC)
- DOE Contract Number:
- AC02-98CH10886
- OSTI ID:
- 1041738
- Report Number(s):
- BNL--97416-2012-JA
- Journal Information:
- Journal of Biological Chemistry, Journal Name: Journal of Biological Chemistry Vol. 285; ISSN JBCHA3; ISSN 0021-9258
- Country of Publication:
- United States
- Language:
- English
Similar Records
Structure and Function of Flavivirus NS5 Methyltransferase
Journal Article
·
Sun Dec 31 23:00:00 EST 2006
· Journal of Virology
·
OSTI ID:930027