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Virus-Receptor Interactions of Glycosylated SARS-CoV-2 Spike and Human ACE2 Receptor.
Cell Host & Microbe ( IF 20.6 ) Pub Date : 2020-08-24 , DOI: 10.1016/j.chom.2020.08.004
Peng Zhao 1 , Jeremy L Praissman 1 , Oliver C Grant 1 , Yongfei Cai 2 , Tianshu Xiao 2 , Katelyn E Rosenbalm 1 , Kazuhiro Aoki 1 , Benjamin P Kellman 3 , Robert Bridger 1 , Dan H Barouch 4 , Melinda A Brindley 5 , Nathan E Lewis 6 , Michael Tiemeyer 1 , Bing Chen 2 , Robert J Woods 1 , Lance Wells 1
Affiliation  

The SARS-CoV-2 betacoronavirus uses its highly glycosylated trimeric Spike protein to bind to the cell surface receptor angiotensin converting enzyme 2 (ACE2) glycoprotein and facilitate host cell entry. We utilized glycomics-informed glycoproteomics to characterize site-specific microheterogeneity of glycosylation for a recombinant trimer Spike mimetic immunogen and for a soluble version of human ACE2. We combined this information with bioinformatics analyses of natural variants and with existing 3D structures of both glycoproteins to generate molecular dynamics simulations of each glycoprotein both alone and interacting with one another. Our results highlight roles for glycans in sterically masking polypeptide epitopes and directly modulating Spike-ACE2 interactions. Furthermore, our results illustrate the impact of viral evolution and divergence on Spike glycosylation, as well as the influence of natural variants on ACE2 receptor glycosylation. Taken together, these data can facilitate immunogen design to achieve antibody neutralization and inform therapeutic strategies to inhibit viral infection.



中文翻译:


糖基化 SARS-CoV-2 刺突和人类 ACE2 受体的病毒-受体相互作用。



SARS-CoV-2 β冠状病毒利用其高度糖基化的三聚刺突蛋白与细胞表面受体血管紧张素转换酶 2 (ACE2) 糖蛋白结合,并促进宿主细胞进入。我们利用糖组学信息的糖蛋白质组学来表征重组三聚体 Spike 模拟免疫原和人 ACE2 可溶版本的糖基化位点特异性微观异质性。我们将这些信息与天然变体的生物信息学分析以及两种糖蛋白的现有 3D 结构相结合,生成每种糖蛋白单独和彼此相互作用的分子动力学模拟。我们的结果强调了聚糖在空间掩蔽多肽表位和直接调节 Spike-ACE2 相互作用中的作用。此外,我们的结果说明了病毒进化和分化对 Spike 糖基化的影响,以及自然变异对 ACE2 受体糖基化的影响。总而言之,这些数据可以促进免疫原设计以实现抗体中和,并为抑制病毒感染的治疗策略提供信息。

更新日期:2020-10-07
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