Structural and functional insights in flavivirus NS5 proteins gained by the structure of Ntaya virus polymerase and methyltransferase

IF 4.4 2区生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Structure Pub Date : 2024-05-22 DOI:10.1016/j.str.2024.04.020

Kateřina Krejčová, Petra Krafcikova, Martin Klima, Dominika Chalupska, Karel Chalupsky, Eva Zilecka, Evzen Boura

引用次数: 0

Abstract

Flaviviruses are single-stranded positive-sense RNA (+RNA) viruses that are responsible for several (re)emerging diseases such as yellow, dengue, or West Nile fevers. The Zika epidemic highlighted their dangerousness when a relatively benign virus known since the 1950s turned into a deadly pathogen. The central protein for their replication is NS5 (non-structural protein 5), which is composed of the N-terminal methyltransferase (MTase) domain and the C-terminal RNA-dependent RNA-polymerase (RdRp) domain. It is responsible for both RNA replication and installation of the 5′ RNA cap. We structurally and biochemically analyzed the Ntaya virus MTase and RdRp domains and we compared their properties to other flaviviral NS5s. The enzymatic centers are well conserved across Flaviviridae, suggesting that the development of drugs targeting all flaviviruses is feasible. However, the enzymatic activities of the isolated proteins were significantly different for the MTase domains.

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通过 Ntaya 病毒聚合酶和甲基转移酶的结构了解黄病毒 NS5 蛋白的结构和功能

黄病毒是单链正义 RNA（+RNA）病毒，是黄热病、登革热或西尼罗河热等几种（新）疾病的元凶。寨卡疫情凸显了它们的危险性，一种自 20 世纪 50 年代以来就为人所知的相对良性的病毒变成了致命的病原体。它们复制的核心蛋白是 NS5（非结构蛋白 5），由 N 端甲基转移酶（MTase）结构域和 C 端 RNA 依赖性 RNA 聚合酶（RdRp）结构域组成。它负责 RNA 复制和 5′ RNA 帽的安装。我们对 Ntaya 病毒 MTase 和 RdRp 结构域进行了结构和生物化学分析，并将它们的特性与其他黄病毒 NS5 进行了比较。这些酶中心在黄病毒科中具有很好的一致性，这表明开发针对所有黄病毒的药物是可行的。然而，分离出的蛋白质的酶活性在 MTase 结构域上有显著差异。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Structure 生物-生化与分子生物学

CiteScore

8.90

自引率

1.80%

发文量

155

审稿时长

3-8 weeks

期刊介绍： Structure aims to publish papers of exceptional interest in the field of structural biology. The journal strives to be essential reading for structural biologists, as well as biologists and biochemists that are interested in macromolecular structure and function. Structure strongly encourages the submission of manuscripts that present structural and molecular insights into biological function and mechanism. Other reports that address fundamental questions in structural biology, such as structure-based examinations of protein evolution, folding, and/or design, will also be considered. We will consider the application of any method, experimental or computational, at high or low resolution, to conduct structural investigations, as long as the method is appropriate for the biological, functional, and mechanistic question(s) being addressed. Likewise, reports describing single-molecule analysis of biological mechanisms are welcome. In general, the editors encourage submission of experimental structural studies that are enriched by an analysis of structure-activity relationships and will not consider studies that solely report structural information unless the structure or analysis is of exceptional and broad interest. Studies reporting only homology models, de novo models, or molecular dynamics simulations are also discouraged unless the models are informed by or validated by novel experimental data; rationalization of a large body of existing experimental evidence and making testable predictions based on a model or simulation is often not considered sufficient.