Structures of the Mononegavirales Polymerases.
Structures of the Mononegavirales Polymerases.
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DOI：
10.1128/jvi.00175-20
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发表时间：
2020-10-27
影响因子：
5.4
通讯作者：
Liang B
中科院分区：
文献类型：
--
作者：
Liang B
单粒病毒又称非分段负义(NNS)RNA病毒，是一类致病性病毒，有时甚至是致命的，包括狂犬病病毒(RABV)、人类呼吸道合胞病毒(HRSV)和埃博拉病毒(EBOV)。不幸的是，目前还没有针对许多单粒子病毒的有效疫苗和抗病毒疗法。病毒聚合酶一直是有吸引力的抗病毒治疗的主要靶点。因此，Mononegavirales聚合酶的结构和功能已被广泛研究。单粒病毒又称非分段负义(NNS)RNA病毒，是一类致病性病毒，有时甚至是致命的，包括狂犬病病毒(RABV)、人类呼吸道合胞病毒(HRSV)和埃博拉病毒(EBOV)。不幸的是，目前还没有针对许多单粒子病毒的有效疫苗和抗病毒疗法。病毒聚合酶一直是有吸引力的抗病毒治疗的主要靶点。因此，Mononegavirales聚合酶的结构和功能已被广泛研究。利用多功能RNA聚合酶复制病毒全基因组，从单个病毒基因转录病毒mRNAs，以及合成转录后的病毒mRNAs的5‘甲基化帽和3’聚(A)尾，从而模拟真核生物的RNA合成。催化亚单位大蛋白(L)和辅因子磷蛋白(P)组成单粒病毒聚合酶。在本文中，我们讨论了核糖核酸合成的共同和独特的特征，单体多功能酶L，以及单胞菌的寡聚体多模块接头P。我们概述了自2015年确定水疱性口炎病毒L蛋白的第一个结构以来的单巨病毒聚合酶的结构分析，并重点介绍了近几个月(2019年至2020年)报道的单巨病毒多聚酶的多个高分辨冷冻电子显微镜结构，即水疱性口炎病毒、RABV、HRSV、人偏肺病毒和人副流感病毒。我们比较了按病毒家族分类的聚合酶的结构，阐明了这些聚合酶的异同，并揭示了高度保守的单核病毒科潜在的RNA合成机制和模式。我们通过对剩余问题、进化观点和未来方向的讨论来结束。
Mononegavirales, known as nonsegmented negative-sense (NNS) RNA viruses, are a class of pathogenic and sometimes deadly viruses that include rabies virus (RABV), human respiratory syncytial virus (HRSV), and Ebola virus (EBOV). Unfortunately, no effective vaccines and antiviral therapeutics against many Mononegavirales are currently available. Viral polymerases have been attractive and major antiviral therapeutic targets. Therefore, Mononegavirales polymerases have been extensively investigated for their structures and functions. Mononegavirales, known as nonsegmented negative-sense (NNS) RNA viruses, are a class of pathogenic and sometimes deadly viruses that include rabies virus (RABV), human respiratory syncytial virus (HRSV), and Ebola virus (EBOV). Unfortunately, no effective vaccines and antiviral therapeutics against many Mononegavirales are currently available. Viral polymerases have been attractive and major antiviral therapeutic targets. Therefore, Mononegavirales polymerases have been extensively investigated for their structures and functions. Mononegavirales mimic RNA synthesis of their eukaryotic counterparts by utilizing multifunctional RNA polymerases to replicate entire viral genomes and transcribe viral mRNAs from individual viral genes as well as synthesize 5′ methylated cap and 3′ poly(A) tail of the transcribed viral mRNAs. The catalytic subunit large protein (L) and cofactor phosphoprotein (P) constitute the Mononegavirales polymerases. In this review, we discuss the shared and unique features of RNA synthesis, the monomeric multifunctional enzyme L, and the oligomeric multimodular adapter P of Mononegavirales. We outline the structural analyses of the Mononegavirales polymerases since the first structure of the vesicular stomatitis virus (VSV) L protein determined in 2015 and highlight multiple high-resolution cryo-electron microscopy (cryo-EM) structures of the polymerases of Mononegavirales, namely, VSV, RABV, HRSV, human metapneumovirus (HMPV), and human parainfluenza virus (HPIV), that have been reported in recent months (2019 to 2020). We compare the structures of those polymerases grouped by virus family, illustrate the similarities and differences among those polymerases, and reveal the potential RNA synthesis mechanisms and models of highly conserved Mononegavirales. We conclude by the discussion of remaining questions, evolutionary perspectives, and future directions.