Structural and functional analyses of a conserved hydrophobic pocket of flavivirus methyltransferase

Hongping Dong, Lihui Liu, Gang Zou, Yiwei Zhao, Zhong Li, Siew Pheng Lim, Pei Yong Shi, Hongmin Li

Research output: Contribution to journalArticle

39 Scopus citations

Abstract

The flavivirus methyltransferase (MTase) sequentially methylates the N7 and 2′-O positions of the viral RNA cap (GpppA-RNA → m 7GpppA-RNA → m7GpppAm-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-Å 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.

Original languageEnglish (US)
Pages (from-to)32586-32595
Number of pages10
JournalJournal of Biological Chemistry
Volume285
Issue number42
DOIs
StatePublished - Oct 15 2010

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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