Structural Analysis of the OC43 Coronavirus 2′-O-RNA Methyltransferase
Structural Analysis of the OC43 Coronavirus 2′-O-RNA Methyltransferase
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DOI：
10.1128/jvi.00463-21
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发表时间：
2021-08-01
影响因子：
5.4
通讯作者：
Boura, Evzen
中科院分区：
文献类型：
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作者：
Dostalik, Pavel;Krafcikova, Petra;Boura, Evzen
OC 43冠状病毒是一种人类病原体，通常只引起普通感冒。与其他冠状病毒相似，其关键酶之一是29-O-RNA甲基转移酶（MTase），该酶对病毒RNA的稳定性和表达至关重要。在这里，我们报告的晶体结构的29-O-RNA MTase在复杂的泛甲基转移酶抑制剂sinefungin解决在2.2-A分辨率。该结构揭示了与在其他冠状病毒MTase中观察到的折叠一致的总体折叠。主要差异在于nsp 16亚基的C末端的构象和nsp 10亚基的N末端的额外螺旋。结构分析还揭示了非常高的保守性的S-腺苷甲硫氨酸（SAM）结合口袋，这表明SAM口袋是一个合适的点设计的抗病毒药物有效地对抗所有人类冠状病毒。重要的一些冠状病毒是危险的病原体，而一些原因只有普通感冒。其原因尚不清楚，尽管刺突蛋白可能起着重要作用。然而，为了足够详细地了解冠状病毒的生物学，我们需要比较不同冠状病毒的关键酶。我们解决了OC 43冠状病毒的29-O-RNA甲基转移酶的晶体结构，这种病毒通常会导致轻度感冒。结构揭示了整体折叠的一些差异，但也揭示了SAM结合位点是保守的，这表明开发针对多种冠状病毒的抗病毒药物是可行的。
The OC43 coronavirus is a human pathogen that usually causes only the common cold. One of its key enzymes, similar to other coronaviruses, is the 29-O-RNA methyltransferase (MTase), which is essential for viral RNA stability and expression. Here, we report the crystal structure of the 29-O-RNA MTase in a complex with the pan-methyltransferase inhibitor sinefungin solved at 2.2-A resolution. The structure reveals an overall fold consistent with the fold observed in other coronaviral MTases. The major differences are in the conformation of the C terminus of the nsp16 subunit and an additional helix in the N terminus of the nsp10 subunits. The structural analysis also revealed very high conservation of the S-adenosyl methionine (SAM) binding pocket, suggesting that the SAM pocket is a suitable spot for the design of antivirals effective against all human coronaviruses.IMPORTANCE Some coronaviruses are dangerous pathogens, while some cause only common colds. The reasons are not understood, although the spike proteins probably play an important role. However, to understand the coronaviral biology in sufficient detail, we need to compare the key enzymes from different coronaviruses. We solved the crystal structure of 29-O-RNA methyltransferase of the OC43 coronavirus, a virus that usually causes mild colds. The structure revealed some differences in the overall fold but also revealed that the SAM binding site is conserved, suggesting that development of antivirals against multiple coronaviruses is feasible.