2oy0

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spinqualitylabelsall models 2oy0, resolution 2.80Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image

Crystal structure of the West Nile virus methyltransferase

Overview

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 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 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.

About this Structure

2OY0 is a Single protein structure of sequence from West nile virus with SAH as ligand. Full crystallographic information is available from OCA.

Reference

Structure and Function of Flavivirus NS5 Methyltransferase., Zhou Y, Ray D, Zhao Y, Dong H, Ren S, Li Z, Guo Y, Bernard KA, Shi PY, Li H, J Virol. 2007 Apr;81(8):3891-903. Epub 2007 Jan 31. PMID:17267492

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