最新！新冠病毒mRNA甲基化逃避宿主免疫机制被阐明

新型冠状病毒在全球肆虐，超300万人感染。

在SARS冠状病毒中，NSP16蛋白甲基化病毒mRNA，模拟人的mRNA修饰，从而逃逸机体天然免疫反应。在SARS-COV-2中如何作用尚不清楚。

4月26日，Yogesh K. Guptad博士等用结构生物学的方法解析了NSP16-NSP10-mRNA三元复合物的高分辨率结构。发现mRNA上的第一个核糖核苷酸的2-O'发生甲基化时，被NSP16-NSP10异源二聚体捕获，并且构象发生较大的改变。

NSP16-NSP10结构

该研究揭示病毒mRNA甲基化的具体机制，发现了潜在的抗病毒位点。

原文摘要：

The novel severe acute respiratory syndrome coronoavirus-2 (SARS-CoV-2), the causative agent of COVID-19 illness, has caused over 2 million infections worldwide in four months. In SARS coronaviruses, the non-structural protein 16 (nsp16) 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 full-length nsp16 and nsp10 of SARS-CoV-2 in the presence of cognate RNA substrate and a methyl donor, S-adenosyl methionine. The nsp16/nsp10 heterodimer was captured in the act of 2’-O methylation of the ribose sugar of the first nucleotide of SARS-CoV-2 mRNA. We reveal large conformational changes associated with substrate binding as the enzyme transitions from a binary to a ternary state. This structure provides new mechanistic insights into the 2’-O methylation of the viral mRNA cap. We also discovered a distantly located ligand-binding site unique to SARS-CoV-2 that may serve as an alternative target site for antiviral development.