Structural and Functional Analyses of a Conserved Hydrophobic Pocket of Flavivirus Methyltransferase
Structural and Functional Analyses of a Conserved Hydrophobic Pocket of Flavivirus Methyltransferase
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DOI：
10.1074/jbc.m110.129197
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发表时间：
2010-10-15
影响因子：
4.8
通讯作者：
Li, Hongmin
中科院分区：
文献类型：
--
作者：
Dong, Hongping;Liu, Lihui;Li, Hongmin
黄病毒甲基转移酶（MTase）使用S-腺苷-L-甲硫氨酸（S-腺苷蛋氨酸）作为甲基供体，依次甲基化病毒RNA帽的N7和2 '-O位置（GpppA-RNA-> m（7）GpppA-RNA -> m（7）GpppAm-RNA）。我们在这里报告，sinefungin（SIN），一种抗甲硫氨酸类似物，通过抑制病毒MTase抑制几种黄病毒。在2.0埃分辨率下，西尼罗病毒MTase与SIN抑制剂复合的晶体结构揭示了位于CIMET结合位点旁边的黄病毒保守的疏水口袋。该口袋在病毒复制和帽甲基化中具有关键的功能。此外，发现N7甲基化效率与病毒复制能力相关。因此，SIN类似物与疏水口袋相互作用的修饰是黄病毒MTase的潜在特异性抑制剂。
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-angstrom 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.