小柯机器人

中国科学院大学存济医学院施一等研究人员合作揭示埃博拉病毒聚合酶从头复制的分子机制。2023年9月12日，《自然》杂志在线发表了这项成果。

研究人员以埃博拉病毒（EBOV）L聚合酶为代表，通过酶切实验表明，L聚合酶的从头复制受EBOV基因组特定3'前导序列的控制，至少三个碱基对的形成可有效驱动RNA合成的延伸过程，而不受特定RNA序列的影响。研究人员随后测定了EBOV L-VP35-RNA复合物的高分辨率结构，发现3'前导RNA以独特的稳定弯曲构象结合在模板入口通道中。

进一步的诱变工作证实了RNA的弯曲构象是从头复制活性所需的，并揭示了L蛋白中稳定RNA构象的关键残基。这些发现为非节段负链RNA病毒（nsNSV）聚合酶的RNA合成提供了新的机理认识，并揭示了开发抗病毒药物的重要靶点。

据介绍，nsNSV，包括EBOV、狂犬病病毒、人类呼吸道合胞病毒和肺炎病毒，可导致人类和动物呼吸道感染、出血热和脑炎，被认为是全球重大的健康和经济负担。病毒基因组的复制和转录是由大型L聚合酶完成的，该聚合酶是开发抗病毒药物的一个很有前景的靶点。

附：英文原文

Title: Molecular mechanism of de novo replication by the Ebola virus polymerase

Author: Peng, Qi, Yuan, Bin, Cheng, Jinlong, Wang, Min, Gao, Siwei, Bai, Suran, Zhao, Xuejin, Qi, Jianxun, Gao, George F., Shi, Yi

Issue&Volume: 2023-09-12

Abstract: Non-segmented negative-strand RNA viruses (nsNSVs) including Ebola virus (EBOV), rabies virus, human respiratory syncytial virus and pneumoviruses can cause respiratory infections, hemorrhagic fever and encephalitis in the humans and animals, and are considered as substantial health and economic burden worldwide1. Replication and transcription of the viral genome are executed by the large L polymerase that is a promising target for the development of antiviral drugs. Here, using EBOV L polymerase as a representative, we showed that de novo replication of L polymerase is controlled by the specific 3’ leader sequence of EBOV genome in an enzymatic assay, and formation of at least three base pairs can effectively drive the elongation process of RNA synthesis independent of the specific RNA sequence. We then determined the high-resolution structures of EBOV L-VP35-RNA complex and found that the 3’ leader RNA binds in the template entry channel with a distinctive stable bend conformation. Further mutagenesis work confirmed that the bend conformation of RNA is required for the de novo replication activity and revealed the key residues of L protein that stabilize the RNA conformation. These findings have provided a new mechanistic understanding of RNA synthesis for nsNSV polymerases, and revealed important targets for the development of antiviral drugs.

DOI: 10.1038/s41586-023-06608-1

Source: https://www.nature.com/articles/s41586-023-06608-1

Nature：《自然》，创刊于1869年。隶属于施普林格·自然出版集团，最新IF：69.504
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