Biology Department, Brookhaven National Laboratory, Upton, NY, USA.
Biochemistry and Cell Biology Department, Stony Brook University, Stony Brook, NY, USA.
Nat Commun. 2021 Jun 8;12(1):3433. doi: 10.1038/s41467-021-23533-x.
The COVID-19 pandemic, caused by the SARS-CoV-2 virus, has created global health and economic emergencies. SARS-CoV-2 viruses promote their own spread and virulence by hijacking human proteins, which occurs through viral protein recognition of human targets. To understand the structural basis for SARS-CoV-2 viral-host protein recognition, here we use cryo-electron microscopy (cryo-EM) to determine a complex structure of the human cell junction protein PALS1 and SARS-CoV-2 viral envelope (E) protein. Our reported structure shows that the E protein C-terminal DLLV motif recognizes a pocket formed exclusively by hydrophobic residues from the PDZ and SH3 domains of PALS1. Our structural analysis provides an explanation for the observation that the viral E protein recruits PALS1 from lung epithelial cell junctions. In addition, our structure provides novel targets for peptide- and small-molecule inhibitors that could block the PALS1-E interactions to reduce E-mediated virulence.
由 SARS-CoV-2 病毒引起的 COVID-19 大流行已经造成了全球卫生和经济紧急情况。SARS-CoV-2 病毒通过劫持人类蛋白质来促进自身的传播和毒力，这是通过病毒蛋白识别人类靶标来实现的。为了了解 SARS-CoV-2 病毒与宿主蛋白识别的结构基础，我们使用冷冻电子显微镜（cryo-EM）来确定人细胞连接蛋白 PALS1 和 SARS-CoV-2 病毒包膜（E）蛋白的复合物结构。我们报告的结构表明，E 蛋白 C 端 DLLV 基序识别一个由 PDZ 和 SH3 结构域的 PALS1 中特有的疏水性残基形成的口袋。我们的结构分析解释了观察到的病毒 E 蛋白从肺上皮细胞连接招募 PALS1 的现象。此外，我们的结构为肽和小分子抑制剂提供了新的靶标，这些抑制剂可以阻断 PALS1-E 相互作用，从而降低 E 介导的毒力。
Zotero 插件