{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T22:48:43Z","timestamp":1791413323913,"version":"4.3.3"},"reference-count":45,"publisher":"American Society for Microbiology","issue":"8","license":[{"start":{"date-parts":[[2007,4,15]],"date-time":"2007-04-15T00:00:00Z","timestamp":1176595200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.asm.org\/non-commercial-tdm-license"}],"content-domain":{"domain":["journals.asm.org"],"crossmark-restriction":true},"short-container-title":["J Virol"],"published-print":{"date-parts":[[2007,4,15]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>\n                    The plus-strand RNA genome of flavivirus contains a 5\u2032 terminal cap 1 structure (m\n                    <jats:sup>7<\/jats:sup>\n                    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\u2032-OH methylations during viral cap formation. Representative flavivirus methyltransferases from dengue, yellow fever, and West Nile virus (WNV) sequentially generate GpppA \u2192 m\n                    <jats:sup>7<\/jats:sup>\n                    GpppA \u2192 m\n                    <jats:sup>7<\/jats:sup>\n                    GpppAm. The 2\u2032-O methylation can be uncoupled from the N-7 methylation, since m\n                    <jats:sup>7<\/jats:sup>\n                    GpppA-RNA can be readily methylated to m\n                    <jats:sup>7<\/jats:sup>\n                    GpppAm-RNA. Despite exhibiting two distinct methylation activities, the crystal structure of WNV methyltransferase at 2.8 A\u030a resolution showed a single binding site for\n                    <jats:italic>S<\/jats:italic>\n                    -adenosyl-\n                    <jats:sc>l<\/jats:sc>\n                    -methionine (SAM), the methyl donor. Therefore, substrate GpppA-RNA should be repositioned to accept the N-7 and 2\u2032-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\u2032-O cap methylations require distinct buffer conditions and different side chains within the K\n                    <jats:sub>61<\/jats:sub>\n                    -D\n                    <jats:sub>146<\/jats:sub>\n                    -K\n                    <jats:sub>182<\/jats:sub>\n                    -E\n                    <jats:sub>218<\/jats:sub>\n                    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\u2032-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.\n                  <\/jats:p>","DOI":"10.1128\/jvi.02704-06","type":"journal-article","created":{"date-parts":[[2007,2,2]],"date-time":"2007-02-02T21:42:26Z","timestamp":1170452546000},"page":"3891-3903","update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":376,"title":["Structure and Function of Flavivirus NS5 Methyltransferase"],"prefix":"10.1128","volume":"81","author":[{"given":"Yangsheng","family":"Zhou","sequence":"first","affiliation":[{"name":"Wadsworth Center, New York State Department of Health"},{"name":"Department of Biomedical Sciences, School of Public Health, State University of New York, Albany, New York 12201"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Debashish","family":"Ray","sequence":"additional","affiliation":[{"name":"Wadsworth Center, New York State Department of Health"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yiwei","family":"Zhao","sequence":"additional","affiliation":[{"name":"Wadsworth Center, New York State Department of Health"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hongping","family":"Dong","sequence":"additional","affiliation":[{"name":"Wadsworth Center, New York State Department of Health"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Suping","family":"Ren","sequence":"additional","affiliation":[{"name":"Wadsworth Center, New York State Department of Health"},{"name":"Department of Biomedical Sciences, School of Public Health, State University of New York, Albany, New York 12201"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhong","family":"Li","sequence":"additional","affiliation":[{"name":"Wadsworth Center, New York State Department of Health"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yi","family":"Guo","sequence":"additional","affiliation":[{"name":"Wadsworth Center, New York State Department of Health"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kristen A.","family":"Bernard","sequence":"additional","affiliation":[{"name":"Wadsworth Center, New York State Department of Health"},{"name":"Department of Biomedical Sciences, School of Public Health, State University of New York, Albany, New York 12201"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pei-Yong","family":"Shi","sequence":"additional","affiliation":[{"name":"Wadsworth Center, New York State Department of Health"},{"name":"Department of Biomedical Sciences, School of Public Health, State University of New York, Albany, New York 12201"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hongmin","family":"Li","sequence":"additional","affiliation":[{"name":"Wadsworth Center, New York State Department of Health"},{"name":"Department of Biomedical Sciences, School of Public Health, State University of New York, Albany, New York 12201"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"235","reference":[{"key":"e_1_3_2_2_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M104248200"},{"key":"e_1_3_2_3_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M400460200"},{"key":"e_1_3_2_4_2","doi-asserted-by":"publisher","DOI":"10.1099\/vir.0.18860-0"},{"key":"e_1_3_2_5_2","doi-asserted-by":"publisher","DOI":"10.1016\/0042-6822(88)90468-0"},{"key":"e_1_3_2_6_2","doi-asserted-by":"publisher","DOI":"10.1107\/S0907444998003254"},{"key":"e_1_3_2_7_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0400660101"},{"key":"e_1_3_2_8_2","doi-asserted-by":"publisher","DOI":"10.1016\/0042-6822(79)90181-8"},{"key":"e_1_3_2_9_2","unstructured":"J. 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