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

34 Citations (Scopus)

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
Externally publishedYes

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sinefungin
Flavivirus
Methyltransferases
S-Adenosylmethionine
Methylation
RNA
RNA Caps
West Nile virus
Viral RNA
Viruses
Crystal structure
Binding Sites

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology

Cite this

Structural and functional analyses of a conserved hydrophobic pocket of flavivirus methyltransferase. / Dong, Hongping; Liu, Lihui; Zou, Gang; Zhao, Yiwei; Li, Zhong; Lim, Siew Pheng; Shi, Pei-Yong; Li, Hongmin.

In: Journal of Biological Chemistry, Vol. 285, No. 42, 15.10.2010, p. 32586-32595.

Research output: Contribution to journalArticle

Dong, Hongping ; Liu, Lihui ; Zou, Gang ; Zhao, Yiwei ; Li, Zhong ; Lim, Siew Pheng ; Shi, Pei-Yong ; Li, Hongmin. / Structural and functional analyses of a conserved hydrophobic pocket of flavivirus methyltransferase. In: Journal of Biological Chemistry. 2010 ; Vol. 285, No. 42. pp. 32586-32595.
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AU - Lim, Siew Pheng

AU - Shi, Pei-Yong

AU - Li, Hongmin

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