Structural insights into the mechanism of RNA recognition by the N-terminal RNA-binding domain of the SARS-CoV-2 nucleocapsid phosphoprotein
Structural insights into the mechanism of RNA recognition by the N-terminal RNA-binding domain of the SARS-CoV-2 nucleocapsid phosphoprotein
复制标题
DOI：
10.1016/j.csbj.2020.08.006
复制
发表时间：
2020-01-01
影响因子：
6
通讯作者：
Wei, Dong-Qing
中科院分区：
文献类型：
--
作者：
Khan, Abbas;Khan, Muhammad Tahir;Wei, Dong-Qing
最近出现的SARS-CoV-2已成为一个全球卫生问题。这种单链正义RNA病毒正在不断传播，发病率和死亡率都在不断增加。该病毒的蛋白质组包含4种结构蛋白和16种非结构蛋白，确保病毒在宿主细胞中复制。然而，磷酸蛋白(N)在RNA识别、复制、转录病毒基因组和调节宿主免疫反应中的作用是不可或缺的。最近，核衣壳蛋白N-末端结构域的核磁共振结构已有报道，但其与单链RNA相互作用的确切结构机制尚未见报道。因此，在这里，我们使用了一个集成的计算管道来识别关键残基，这些残基在RNA识别中起着至关重要的作用。我们使用丙氨酸扫描策略生成了多个变体，并对每个系统进行了广泛的模拟，以表示每个界面残基的作用。我们的分析表明，T57A、H59A、S105A、R107A、F171A和Y172A残基对RNA的动力学和结合有显著影响。此外，每残基能量分解分析表明，T57、H59、S105和R107残基是药物发现的关键热点。因此，这些残基可能在药物设计中作为潜在的药效团有用。(C)2020年提交人(S)。由Elsevier B.V.代表计算和结构生物技术研究网络出版。
The emergence of recent SARS-CoV-2 has become a global health issue. This single-stranded positive-sense RNA virus is continuously spreading with increasing morbidities and mortalities. The proteome of this virus contains four structural and sixteen nonstructural proteins that ensure the replication of the virus in the host cell. However, the role of phosphoprotein (N) in RNA recognition, replicating, transcribing the viral genome, and modulating the host immune response is indispensable. Recently, the NMR structure of the N-terminal domain of the Nucleocapsid Phosphoprotein has been reported, but its precise structural mechanism of how the ssRNA interacts with it is not reported yet. Therefore, here, we have used an integrated computational pipeline to identify the key residues, which play an essential role in RNA recognition. We generated multiple variants by using an alanine scanning strategy and performed an extensive simulation for each system to signify the role of each interfacial residue. Our analyses suggest that residues T57A, H59A, S105A, R107A, F171A, and Y172A significantly affected the dynamics and binding of RNA. Furthermore, per-residue energy decomposition analysis suggests that residues T57, H59, S105 and R107 are the key hotspots for drug discovery. Thus, these residues may be useful as potential pharmacophores in drug designing. (C) 2020 The Author(s). Published by Elsevier B.V. on behalf of Research Network of Computational and Structural Biotechnology.