The DOI matches its Crossref record; 33 of the 33 references it cites were found in a registry or an index.
Structure and Function of Flavivirus NS5 Methyltransferase
Open accessAbstract
The plus-strand RNA genome of flavivirus contains a 5′ terminal cap 1 structure (m 7 GpppAmG). 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 → m 7 GpppA → m 7 GpppAm. The 2′-O methylation can be uncoupled from the N-7 methylation, since m 7 GpppA-RNA can be readily methylated to m 7 GpppAm-RNA. Despite exhibiting two distinct methylation activities, the crystal structure of WNV methyltransferase at 2.8 Å 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 K 61 -D 146 -K 182 -E 218 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.
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Cited by
2′-O methylation of the viral mRNA cap evades host restriction by IFIT family members
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Self-citationIn Vitro Reconstitution of SARS-Coronavirus mRNA Cap Methylation
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Biochemistry and Molecular Biology of Flaviviruses
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Metadata
- Authors
- Zhou, Y., Ray, D., Zhao, Y., Dong, H., Ren, S., Li, Z., Guo, Y., Bernard, K. A., Shi, P.-Y., & Li, H.
- Venue
- Journal of Virology
- Publisher
- American Society for Microbiology
- Published
- 2007-04-15
- Volume
- 81
- Issue
- 8
- Pages
- 3891-3903
- ISSN
- 0022-538X (ISSN-L)
- 1098-5514
- OpenAlex
- W2152181056
- Cited by
- 406
- References
- 33
- FWCI
- 24.97
- Type
- journal article
- Language
- en
- Open access
- green
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