據(jù)悉,，從武漢大學(xué)基礎(chǔ)醫(yī)學(xué)院郭德銀教授研究組的一篇題為《從生化和結(jié)構(gòu)視角深入揭示SARS冠狀病毒RNA甲基化機制》的學(xué)術(shù)論文,，最近發(fā)表在國際病毒學(xué)領(lǐng)域權(quán)威期刊《公共科學(xué)圖書館 病原卷》上。這一研究成果揭示了RNA基因組復(fù)制和RNA病毒致病分子機制,，為新型抗病毒藥物的設(shè)計和篩選提供了重要依據(jù),。
該論文是由該院現(xiàn)代病毒研究中心、病毒學(xué)國家重點實驗室郭德銀領(lǐng)導(dǎo)的研究組完成的,，共同第一作者為武漢大學(xué)生命科學(xué)學(xué)院青年教師陳宇和研究生蘇測洋,，中科院院士、著名病毒學(xué)家田波亦為作者之一,。
據(jù)悉,，郭德銀領(lǐng)導(dǎo)的研究組一直堅持研究SARS病毒的復(fù)制與致病機理。2009年率先發(fā)現(xiàn)并鑒定SARS病毒復(fù)制活動中至關(guān)重要的基因組甲基化修飾功能，并在國際著名學(xué)術(shù)期刊《美國科學(xué)院院報》發(fā)表論文,。
研究發(fā)現(xiàn),，RNA病毒復(fù)制過程與以DNA為遺傳基礎(chǔ)的DNA病毒和細胞形態(tài)生命形式有明顯不同。由于RNA基因組復(fù)制酶缺乏糾錯功能,，因此,，RNA病毒變異率較高，容易產(chǎn)生抗藥性或使疫苗失去免疫效果,。郭德銀開展的研究聚焦于SARS病毒RNA甲基化修飾和免疫逃逸直接相關(guān)的另一個甲基轉(zhuǎn)移酶（2’-O-MTase）,。通過生化分析與解析SARS病毒蛋白復(fù)合體（nsp16/nsp10/SAM）晶體結(jié)構(gòu)，深入揭示了這一甲基轉(zhuǎn)移酶的功能機制,，有助于研制短肽或小分子化合物抑制該復(fù)合體形成,，進而抑制SARS病毒的感染與致病，為研發(fā)抗SARS病毒新型特異性藥物提供新途徑,。(生物谷 Bioon.com)
doi:10.1371/journal.ppat.1002294
PMC:
PMID:
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.
