Structural basis of RNA cap modification by SARS-CoV-2
Structural basis of RNA cap modification by SARS-CoV-2
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DOI：
10.1038/s41467-020-17496-8
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发表时间：
2020-07-24
影响因子：
16.6
通讯作者：
Gupta, Yogesh K.
中科院分区：
文献类型：
--
作者：
Viswanathan, Thiruselvam;Arya, Shailee;Gupta, Yogesh K.
严重急性呼吸综合征冠状病毒-2 (SARS-CoV-2) 是 COVID-19 疾病的病原体，已在全球范围内造成数以百万计的感染。在 SARS 冠状病毒中，非结构蛋白 16 (nsp16) 与 nsp10 结合，甲基化病毒编码 mRNA 的 5 端以模仿细胞 mRNA，从而保护病毒免受宿主先天免疫限制。我们在此报告了在同源 RNA 底物类似物和甲基供体 S-腺苷甲硫氨酸 (SAM) 存在下 SARS-CoV-2 nsp16 和 nsp10 三元复合物的高分辨率结构。 nsp16/nsp10 异二聚体是在 SARS-CoV-2 mRNA 第一个核苷酸的核糖 2'-O 甲基化过程中被捕获的。当酶从二元状态转变为三元状态时，我们观察到与底物结合相关的大构象变化。这种诱导拟合模型提供了对病毒 mRNA 帽 2'-O 甲基化的机制见解。我们还发现了 SARS-CoV-2 特有的一个遥远的（25 埃）配体结合位点，除了 RNA 帽和 SAM 口袋之外，该位点也可以作为抗病毒开发的靶点。 p id=Par SARS 冠状病毒的特异性非结构蛋白 (nsp) 参与病毒编码 mRNA 的甲基化，以模仿细胞 mRNA，从而防止宿主先天免疫限制。在这里，作者展示了在同源 RNA 底物类似物和甲基供体 S-腺苷甲硫氨酸存在下 SARS-CoV-2 nsp16/nsp10 三元复合物的高分辨率结构，揭示了独特的配体结合位点，可能代表抗病毒开发的替代靶点。
The severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), the causative agent of COVID-19 illness, has caused millions of infections worldwide. In SARS coronaviruses, the non-structural protein 16 (nsp16), in conjunction with nsp10, methylates the 5-end of virally encoded mRNAs to mimic cellular mRNAs, thus protecting the virus from host innate immune restriction. We report here the high-resolution structure of a ternary complex of SARS-CoV-2 nsp16 and nsp10 in the presence of cognate RNA substrate analogue and methyl donor, S-adenosyl methionine (SAM). The nsp16/nsp10 heterodimer is captured in the act of 2 ' -O methylation of the ribose sugar of the first nucleotide of SARS-CoV-2 mRNA. We observe large conformational changes associated with substrate binding as the enzyme transitions from a binary to a ternary state. This induced fit model provides mechanistic insights into the 2 ' -O methylation of the viral mRNA cap. We also discover a distant (25 angstrom) ligand-binding site unique to SARS-CoV-2, which can alternatively be targeted, in addition to RNA cap and SAM pockets, for antiviral development. p id=Par Specific non-structural proteins (nsp) of SARS coronaviruses are involved in methylation of virally encoded mRNAs to mimic cellular mRNAs for protection against host innate immune restriction. Here, the authors present a high resolution structure of SARS-CoV-2 nsp16/nsp10 ternary complex in the presence of cognate RNA substrate analogue and methyl donor, S-adenosyl methionine, revealing unique ligand-binding sites that may represent alternative targets for antiviral development.