National Clinical Research Center for Geriatrics, and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan, China.
National Clinical Research Center for Geriatrics, and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan, China.
Bioorg Med Chem Lett. 2024 Dec 1;114:130014. doi: 10.1016/j.bmcl.2024.130014. Epub 2024 Nov 1.
The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) nucleocapsid (N) protein performs multiple functions during the viral life cycle, particularly in binding to the viral genomic RNA to form a helical ribonucleoprotein complex. Here, we present that the C-terminal domain of SARS-CoV-2 N protein (N-CTD) specifically interacts with polyguanylic acid (poly(G)). The crystal structure of the N-CTD in complex with 5'-guanylic acid (GMP, also known as guanosine monophosphate) was determined at a resolution of approximately 2.0 Å. A novel GMP-binding pocket in the N-CTD was illustrated. Residues Arg259 and Lys338 were identified to play key roles in binding to GMP through mutational analysis. These two residues are absolutely conserved in the other two highly pathogenic CoVs, SARS-CoV and Middle East respiratory syndrome coronavirus (MERS-CoV). Overall, our findings expand the structural information on N protein interacting with guanylate and reveal a conserved GMP-binding pocket as a potential antiviral target.
严重急性呼吸综合征冠状病毒 2（SARS-CoV-2）核衣壳（N）蛋白在病毒生命周期中执行多种功能，特别是在与病毒基因组 RNA 结合形成螺旋核糖核蛋白复合物方面。在这里，我们提出 SARS-CoV-2 N 蛋白的 C 末端结构域（N-CTD）特异性地与聚鸟苷酸（poly(G)）相互作用。通过大约 2.0 Å 的分辨率确定了 N-CTD 与 5'-鸟苷酸（GMP，也称为鸟苷一磷酸）形成复合物的晶体结构。描绘了 N-CTD 中一个新的 GMP 结合口袋。通过突变分析鉴定出残基 Arg259 和 Lys338 在与 GMP 结合中起关键作用。这两个残基在另外两种高致病性 CoV（SARS-CoV 和中东呼吸综合征冠状病毒（MERS-CoV））中是完全保守的。总的来说，我们的研究结果扩展了 N 蛋白与鸟苷酸相互作用的结构信息，并揭示了一个保守的 GMP 结合口袋作为潜在的抗病毒靶点。
