据悉，从武汉大学基础医学院郭德银教授研究组的一篇题为《从生化和结构视角深入揭示SARS冠状病毒RNA甲基化机制》的学术论文，最近发表在国际病毒学领域权威期刊《公共科学图书馆 病原卷》上。这一研究成果揭示了RNA基因组复制和RNA病毒致病分子机制，为新型抗病毒药物的设计和筛选提供了重要依据。
该论文是由该院现代病毒研究中心、病毒学国家重点实验室郭德银领导的研究组完成的，共同第一作者为武汉大学生命科学学院青年教师陈宇和研究生苏测洋，中科院院士、著名病毒学家田波亦为作者之一。
据悉，郭德银领导的研究组一直坚持研究SARS病毒的复制与致病机理。2009年率先发现并鉴定SARS病毒复制活动中至关重要的基因组甲基化修饰功能，并在国际著名学术期刊《美国科学院院报》发表论文。
研究发现，RNA病毒复制过程与以DNA为遗传基础的DNA病毒和细胞形态生命形式有明显不同。由于RNA基因组复制酶缺乏纠错功能，因此，RNA病毒变异率较高，容易产生抗药性或使疫苗失去免疫效果。郭德银开展的研究聚焦于SARS病毒RNA甲基化修饰和免疫逃逸直接相关的另一个甲基转移酶（2’-O-MTase）。通过生化分析与解析SARS病毒蛋白复合体（nsp16/nsp10/SAM）晶体结构，深入揭示了这一甲基转移酶的功能机制，有助于研制短肽或小分子化合物抑制该复合体形成，进而抑制SARS病毒的感染与致病，为研发抗SARS病毒新型特异性药物提供新途径。(生物谷 Bioon.com)
doi:10.1371/journal.ppat.1002294
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Biochemical and Structural Insights into the Mechanisms of SARS Coronavirus RNA Ribose 2′-O-Methylation by nsp16/nsp10 Protein Complex
Yu Chen, Ceyang Su, Min Ke, Xu Jin, Lirong Xu, Zhou Zhang, Andong Wu, Ying Sun, Zhouning Yang, Po Tien, Tero Ahola, Yi Liang, Xinqi Liu, Deyin Guo
The 5′-cap structure is a distinct feature of eukaryotic mRNAs, and eukaryotic viruses generally modify the 5′-end of viral RNAs to mimic cellular mRNA structure, which is important for RNA stability, protein translation and viral immune escape. SARS coronavirus (SARS-CoV) encodes two S-adenosyl-L-methionine (SAM)-dependent methyltransferases (MTase) which sequentially methylate the RNA cap at guanosine-N7 and ribose 2′-O positions, catalyzed by nsp14 N7-MTase and nsp16 2′-O-MTase, respectively. A unique feature for SARS-CoV is that nsp16 requires non-structural protein nsp10 as a stimulatory factor to execute its MTase activity. Here we report the biochemical characterization of SARS-CoV 2′-O-MTase and the crystal structure of nsp16/nsp10 complex bound with methyl donor SAM. We found that SARS-CoV nsp16 MTase methylated m7GpppA-RNA but not m7GpppG-RNA, which is in contrast with nsp14 MTase that functions in a sequence-independent manner. We demonstrated that nsp10 is required for nsp16 to bind both m7GpppA-RNA substrate and SAM cofactor. Structural analysis revealed that nsp16 possesses the canonical scaffold of MTase and associates with nsp10 at 1:1 ratio. The structure of the nsp16/nsp10 interaction interface shows that nsp10 may stabilize the SAM-binding pocket and extend the substrate RNA-binding groove of nsp16, consistent with the findings in biochemical assays. These results suggest that nsp16/nsp10 interface may represent a better drug target than the viral MTase active site for developing highly specific anti-coronavirus drugs.
