Crystal structure of the CoV-Y domain of SARS-CoV-2 nonstructural protein 3.
Crystal structure of the CoV-Y domain of SARS-CoV-2 nonstructural protein 3.
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DOI：
10.1038/s41598-023-30045-9
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发表时间：
2023-02-18
影响因子：
4.6
通讯作者：
Hao B
中科院分区：
文献类型：
--
作者：
Li Y;Pustovalova Y;Shi W;Gorbatyuk O;Sreeramulu S;Schwalbe H;Hoch JC;Hao B
冠状病毒基因组的复制始于病毒进入宿主细胞后形成含rna的双膜囊泡（DMV）。多结构域非结构蛋白3 （nsp3）是已知冠状病毒基因组编码的最大蛋白，是病毒复制和转录机制的核心组成部分。先前的研究表明，nsp3的高度保守的c端区域对亚细胞膜重排至关重要，但其潜在的机制尚不清楚。在这里，我们报告了SARS-CoV-2 nsp3的最c端结构域CoV-Y结构域的晶体结构，在2.4 Å-resolution。CoV-Y采用先前未表征的v形褶皱，具有三个不同的子结构域。序列比对和结构预测表明，该褶皱可能与密切相关的nsp3同源CoV-Y结构域共享。基于核磁共振的片段筛选结合分子对接鉴定了CoV-Y与潜在配体和其他nsps相互作用的表面空腔。这些研究首次提供了完整的nsp3 CoV-Y结构域的结构视图，并为理解nsp3 c端结构域在冠状病毒复制中的结构、组装和功能提供了分子框架。我们的工作阐明了nsp3作为治疗干预的潜在目标，以帮助对抗COVID-19大流行和其他冠状病毒引起的疾病。
Replication of the coronavirus genome starts with the formation of viral RNA-containing double-membrane vesicles (DMV) following viral entry into the host cell. The multi-domain nonstructural protein 3 (nsp3) is the largest protein encoded by the known coronavirus genome and serves as a central component of the viral replication and transcription machinery. Previous studies demonstrated that the highly-conserved C-terminal region of nsp3 is essential for subcellular membrane rearrangement, yet the underlying mechanisms remain elusive. Here we report the crystal structure of the CoV-Y domain, the most C-terminal domain of the SARS-CoV-2 nsp3, at 2.4 Å-resolution. CoV-Y adopts a previously uncharacterized V-shaped fold featuring three distinct subdomains. Sequence alignment and structure prediction suggest that this fold is likely shared by the CoV-Y domains from closely related nsp3 homologs. NMR-based fragment screening combined with molecular docking identifies surface cavities in CoV-Y for interaction with potential ligands and other nsps. These studies provide the first structural view on a complete nsp3 CoV-Y domain, and the molecular framework for understanding the architecture, assembly and function of the nsp3 C-terminal domains in coronavirus replication. Our work illuminates nsp3 as a potential target for therapeutic interventions to aid in the on-going battle against the COVID-19 pandemic and diseases caused by other coronaviruses.
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