Structure and function of flavivirus NS5 methyltransferase.

Structure and function of flavivirus NS5 methyltransferase. Research Abstract Details 

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Structure and function of flavivirus NS5 methyltransferase. Abstract Text:

Yangsheng Zhou,Debashish Ray,Yiwei Zhao,Hongping Dong,Suping Ren,Zhong Li,Yi Guo,Kristen A Bernard,Pei-Yong Shi,Hongmin Li,

The plus-strand RNA genome of flavivirus contains a 5' terminal cap 1 structure (m7GpppAmG). The flaviviruses encode one methyltransferase, located at the N-terminal portion of the NS5 protein, to catalyze both guanine N-7 and ribose 2'-OH methylations during viral cap formation. Representative flavivirus methyltransferases from dengue, yellow fever, and West Nile virus (WNV) sequentially generate GpppA-->m7GpppA-->m7GpppAm. The 2'-O methylation can be uncoupled from the N-7 methylation, since m7GpppA-RNA can be readily methylated to m7GpppAm-RNA. Despite exhibiting two distinct methylation activities, the crystal structure of WNV methyltransferase at 2.8 A resolution showed a single binding site for S-adenosyl-L-methionine (SAM), the methyl donor. Therefore, substrate GpppA-RNA should be repositioned to accept the N-7 and 2'-O methyl groups from SAM during the sequential reactions. Electrostatic analysis of the WNV methyltransferase structure showed that, adjacent to the SAM-binding pocket, is a highly positively charged surface that could serve as an RNA binding site during cap methylations. Biochemical and mutagenesis analyses show that the N-7 and 2'-O cap methylations require distinct buffer conditions and different side chains within the K61-D146-K182-E218 motif, suggesting that the two reactions use different mechanisms. In the context of complete virus, defects in both methylations are lethal to WNV; however, viruses defective solely in 2'-O methylation are attenuated and can protect mice from later wild-type WNV challenge. The results demonstrate that the N-7 methylation activity is essential for the WNV life cycle and, thus, methyltransferase represents a novel target for flavivirus therapy.

Structure and function of flavivirus NS5 methyltransferase. Publishing Authors By Initials

Y Zhou,D Ray,Y Zhao,H Dong,S Ren,Z Li,Y Guo,KA Bernard,PY Shi,H Li,

For similar viruses: rna viruses: flaviviridae: flavivirus: yellow fever virus research abstracts see: viruses: rna viruses: flaviviridae: flavivirus: yellow fever virus research

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Structure and function of flavivirus NS5 methyltransferase. Journal Published:

PUBLICATION TYPE: Research Support, U.S. Gov't,

Journal: Journal of virology

VOLUME: 81

Page Numbers: 3891-903

Journal Abbreviation: J. Virol.

ISSN: 0022-538X

DAY: 31

MONTH: 01

YEAR: 2007

Structure and function of flavivirus NS5 methyltransferase. Information

Number of References:

LANGUAGE: eng

NlmUniqueID: 113724

Structure and function of flavivirus NS5 methyltransferase. Keywords Mesh Terms:

KEYWORDS: Yellow fever virus

MESH TERMS: chemistry

Chemical & Substance for Abstract: Structure and function of flavivirus NS5 methyltransferase. Information

Substance Name: Methyltransferases

Registry Number: EC 2.1.1.-

Grant and Affiliation Information for Structure and function of flavivirus NS5 methyltransferase.

AFFILIATION: Wadsworth Center, New York State Department of Health, 120 New Scotland Ave., Albany, NY 12208, USA.

Country: United States

AGENCY: United States NIAID

GRANT: U54 AI05 7158

ACRONYM: AI

MEDLINETA: J Virol

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