Structure and function of flavivirus NS5 methyltransferase.
|
Structure and function of flavivirus NS5 methyltransferase.
|
Search TravelDoctorOnline |
Authors: Zhou Y,Ray D,Zhao Y,Dong H,Ren S,Li Z,Guo Y,Bernard KA,Shi PY,Li H,
Address: Wadsworth Center, New York State Department of Health, 120 New Scotland Ave., Albany, NY 12208, USA.
Journal: J Virol.
Publication: 2007 Apr;81(8):3891-903. Epub 2007 Jan 31.
Free Text: Structure and function of flavivirus NS5 methyltransferase.
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.
TraveldoctorOnline 2001 • Disclaimer • webmaster
The contents within traveldoctoronline are presented only for informational purposes and cannot substitute for professional health care or any other medical treatment.All users of this website with health problems should be oblige always to consult their medical doctor before starting any treatment.
