圖1.SARS-CoV-2 RNA nsp16(青色)/nsp10(米色)之複合物，在具有RNA-端帽(RNAcap，紅色)及S-腺苷甲硫氨酸(藍色)之複合體中的三元複合體結構。 (圖援用自原文)
Structure of the ternary complex of SARS-CoV-2 RNA nsp16 (cyan)/nsp10 (beige) in complex with RNA cap (red) and S-adenosyl methionine or SAM (blue).
As we all know too well, the virus SARS-CoV-2 causes the severe respiratory illness COVID-19. In parallel with the critical search for a cure, scientists are working diligently to develop effective treatments that can help lower the morbidity of this deadly virus.
眾所周知，第二型嚴重急性呼吸系統徵候群-冠狀病毒(SARS-CoV-2：Severe Acute Respiratory Syndrome Coronavirus-2)，這種病毒引發2019冠狀病毒症(COVID-19：Coronavirus Disease-19)，這種嚴重呼吸系統疾病。在與尋求關鍵性療法平行進行時，科學家們正努力開發，能有助於降低此致命病毒發病率的有效療法。
To develop these therapeutics, we must understand how the virus is able to invade a host’s cells and dodge detection. A recent Nature Communications report based on research carried out at the U.S. Department of Energy’s Advanced Photon Source (APS) reveals key details about how SARS-CoV-2 modifies its messenger RNA and evades immune responses in its host.
為了開發此些療法，必需瞭解該種病毒如何能，入侵宿主細胞及規避檢測。 根據以美國能源部所屬先進光子源(APS)所進行，最近發表於《自然•期刊通訊》的一項研究，揭露了有關SARS-CoV-2如何，修飾其信使RNA，及避開，於其宿主中之免疫反應的關鍵細節。
Using high-resolution x-ray crystallography, the researchers determined a high-resolution structure of the ternary SARS-CoV-2 RNA cap/nsp16/nsp10 complex and the conformational changes that catalytic nsp16 undergoes during RNA cap-binding. The researchers also discovered a distantly located ligand-binding site that allows nsp16 to bind small molecules outside the catalytic pocket.
使用高解析度的X-射線結晶技術，此些研究人員確認了，三元SARS-CoV-2 RNA cap/nsp16/nsp10複合體的高解析度結構，及在RNA cap結合期間，觸發nsp16經歷的形態變化。此些研究人員也發現一處，使nsp16得以在該觸發區域外部結合小分子，座落於遠處的配位體結合位點。
These findings improve our understanding of mRNA capping in coronaviruses and provide a strategy by which scientists could develop small-molecule drugs that will fight and treat the diseases caused by coronaviruses like SARS-CoV-2.
這些研究發現改善了人們有關，在冠狀病毒中，mRNA加端帽的瞭解，且提供了一種，科學家們可能藉以，開發能對抗及治療，由諸如SARS-CoV-2冠狀病毒，引發之疾病的小分子藥物策略。
Coronaviruses (CoVs) are enveloped positive-sense RNA viruses that are notorious for causing a variety of diseases from enteritis to respiratory illnesses in both animals and humans.
冠狀病毒(CoVs)是於動物及人類中，引發從腸炎到呼吸道各種疾病，惡名昭彰之有包膜的陽性RNA病毒。
The latest SARS-CoV-2 pandemic illustrates how CoVs can jump between species, gain access to host cells, and propagate with little inhibition. But, in order to design vaccines and treatments that will reduce the burden of the diseases caused by coronaviruses, we must understand their immunopathology.
最近SARS-CoV-2的大流行病說明了，CoVs如何能在物種之間跳越、獲得進入宿主細胞的途徑及鮮少受抑制地傳播。不過，為了設計能減少，由冠狀病毒引起之疾病負擔的疫苗及療法，咱們必須瞭解其免疫病理原理。
SARS-CoV-2 is a β-coronavirus that virally encodes mRNAs to mimic host cellular mRNA. To do this, the non-structural protein 16 (nsp16), together with nsp10, methylates the 5′-end of virally encoded mRNAs. Then, nsp16/nsp10 complex converts the mRNA species to the cap-1 form via 2′-O methylation of the ribose sugar of the first nucleotide.
SARS-CoV-2是一種，病毒性編碼mRNA，來模倣宿主細胞mRNA的β-冠狀病毒。為此，非結構蛋白16 (nsp16)與nsp10一起，甲基化病毒性編碼之mRNA的5'-端。之後，nsp16/nsp10複合體經由，第一個核苷酸之核糖的2'-O甲基化，將這種mRNA轉化為端帽-1(cap-1)的形態。
So, what information is missing? In short, the catalytic mechanism of mRNA capping is still unclear. Previous reports have presented crystal structures for SARS-CoV nsp16/nsp10 in complex with the methyl donor S-adenosyl methionine (SAM) without an RNA cap. However, no high-resolution structures had been reported for SARS-CoV-2 nsp16/nsp10 in complex with SAM, the methyl donor, and RNA cap m7GpppA. That is, until recently.
那麼，缺少什麼信息？簡言之，mRNA加端帽的觸發機制，仍然不詳。先前的報告已經提出了，SARS-CoV nsp16 / nsp10具有，無RNA端帽之甲基施體S-腺苷甲硫氨酸(SAM)複合體的晶體結構。不過，未曾具有SAM、甲基施體及RNA端帽m7GpppA之SARS-CoV-2 nsp16 / nsp10複合體的高解析度報告。也就是說，直到最近皆沒有。
The researchers in this study, from University of Texas Health at San Antonio, New England Biolabs, and the Texas Biomedical Research Institute, employed high-brightness x-rays from the APS at the Northeastern Collaborative Access Team (NE-CAT) 24-ID-C beamline to collect the high-resolution x-ray crystallography data on crystals of the nsp16/nsp10/SAM/Cap-O/adenosine complex. (The APS is an Office of Science user facility at Argonne National Laboratory.)
在該項研究中，來自美國德州大學聖安東尼奧醫學中心、新英格蘭生物實驗室及德克薩斯生物醫學研究所的研究人員們採用了，來自Northeastern Collaborative Access Team (NE-CAT)之先進光子源(APS：Advanced Photon Source )24-ID-C光束線的高亮度X-射線，來收集有關nsp16 / nsp10 / SAM / Cap-O /腺苷複合物晶體之高解析度的X-射線晶體學數據。(APS是美國能源部科學局於阿爾岡國家實驗室的用戶設備)
With the data collected at NE-CAT, the researchers were able to determine the high-resolution structure of the ternary complex of SARS-CoV-2 RNA cap/nsp16/nsp10 complex captured just before ribose 2′-O methylation. A representation of this structure is shown in Fig. 1. They observed that during RNA cap-binding, the catalytic nsp16 undergoes a conformational change from a binary to ternary state.
利用在NE-CAT收集的數據，此些研究人員能確認，就在核糖2'-O甲基化之前捕獲之SARS-CoV-2 RNA cap / nsp16 / nsp10三元複合體的高解析度結構。 於圖1.中，呈現了這種結構。他們觀察到，在結合RNA端帽期間，觸發之nsp16經歷了，從二元態到三元態的構象變化。
This transition facilitates the addition of a cap-1 structure, m7GpppNm, which acts as a camouflage for the viral mRNA. As a result, the host cells are tricked into recognizing the viral mRNA as their own. This discovery is especially important because it demonstrates how SARS-CoV-2 can avoid detection by the host’s immune system.
此轉變促進了端帽-1結構物(m7GpppNm)的增添。該結構充當了，病毒mRNA的一種偽裝。結果，宿主細胞被誘騙，將病毒mRNA識別為其自身物。此發現特別重要。因為，這證明了SARS-CoV-2如何避免，被宿主免疫系統偵測到。
The researchers also discovered a distantly located ligand-binding site in nsp16/10 where small molecules can bind outside the catalytic pocket. The findings may help to guide the development of SARS-CoV-2 therapies. In essence, if scientists are able to design small-molecule drugs that prohibit cap-1 structure addition by nsp16, they can eliminate the “camouflage’ effect and expose the virus to host immune restriction.
此些研究人員在nsp16/10中，也發現一處在此觸發區域外部，小分子能結合之座落於遠處的配位體結合位點。這些研究發現可能有助於，引導開發SARS-CoV-2的療法。基本上，倘若科學家們能設計出抑制，由nsp16增添之端帽-1結構物的小分子藥物，則他們能消除上述“偽裝”作用，而使病毒暴露於宿主的免疫束縛中。
The structural details gleaned from this research provide a clearer picture of mRNA capping in coronaviruses. These findings improve our collective understanding of how SARSCoV-2 replicates and avoids detection.
從這項研究收集到的結構細節提供了，在冠狀病毒中，mRNA加端帽的更清晰影像。此些發現改善了人們，對於SARSCoV-2如何，複製及避開被發現的總體瞭解。
原文網址：https://aps.anl.gov/APS-Science-Highlight/2020-08-26/how-sars-cov-2-rna-evades-host-immune-responses
翻譯：許東榮
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