title: Structural and functional analyses of a conserved hydrophobic pocket of flavivirus methyltransferase.
abstract: The flavivirus methyltransferase (MTase) sequentially methylates the N7 and 2'-O positions of the viral RNA cap (GpppA-RNA → m(7)GpppA-RNA → m(7)GpppAm-RNA), using S-adenosyl-l-methionine (AdoMet) as a methyl donor. We report here that sinefungin (SIN), an AdoMet analog, inhibits several flaviviruses through suppression of viral MTase. The crystal structure of West Nile virus MTase in complex with SIN inhibitor at 2.0-Å resolution revealed a flavivirus-conserved hydrophobic pocket located next to the AdoMet-binding site. The pocket is functionally critical in the viral replication and cap methylations. In addition, the N7 methylation efficiency was found to correlate with the viral replication ability. Thus, SIN analogs with modifications that interact with the hydrophobic pocket are potential specific inhibitors of flavivirus MTase.
authors.affiliation: Wadsworth Center, New York State Department of Health, Albany, New York 12201, USA.
authors.forename: Hongping
authors.initials: H
authors.lastname: Dong
authors.forename: Lihui
authors.initials: L
authors.lastname: Liu
authors.forename: Gang
authors.initials: G
authors.lastname: Zou
authors.forename: Yiwei
authors.initials: Y
authors.lastname: Zhao
authors.forename: Zhong
authors.initials: Z
authors.lastname: Li
authors.forename: Siew Pheng
authors.initials: SP
authors.lastname: Lim
authors.forename: Pei-Yong
authors.initials: PY
authors.lastname: Shi
authors.forename: Hongmin
authors.initials: H
authors.lastname: Li
mesh_terms: D000241:Adenosine / Q000031:analogs & derivatives / Q000737:chemistry; D000595:Amino Acid Sequence; D000818:Animals; D000935:Antifungal Agents / Q000737:chemistry; D001665:Binding Sites; D018360:Crystallography, X-Ray; D005416:Flavivirus / Q000201:enzymology*; D006801:Humans; D008780:Methyltransferases / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D008958:Models, Molecular; D008969:Molecular Sequence Data; D015394:Molecular Structure; D017434:Protein Structure, Tertiary; D012315:RNA Caps / Q000737:chemistry; D012367:RNA, Viral / Q000737:chemistry / Q000378:metabolism; D014902:West Nile virus / Q000201:enzymology
chemical_list: D000935:Antifungal Agents; D012315:RNA Caps; D012367:RNA, Viral; D008780:Methyltransferases; D000241:Adenosine; C006235:sinefungin