Structural and functional analyses of a conserved hydrophobic pocket of flavivirus methyltransferase.
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.
Dong
Hongping
H
Wadsworth Center, New York State Department of Health, Albany, New York 12201, USA.
Liu
Lihui
L
Zou
Gang
G
Zhao
Yiwei
Y
Li
Zhong
Z
Lim
Siew Pheng
SP
Shi
Pei-Yong
PY
Li
Hongmin
H
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
D000935:Antifungal Agents; D012315:RNA Caps; D012367:RNA, Viral; D008780:Methyltransferases; D000241:Adenosine; C006235:sinefungin