Controlling the SARS-CoV-2 spike glycoprotein conformation
Controlling the SARS-CoV-2 spike glycoprotein conformation
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DOI：
10.1101/2020.05.18.102087
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发表时间：
2020-07-22
影响因子：
16.8
通讯作者：
Acharya, Priyamvada
中科院分区：
文献类型：
--
作者：
Henderson, Rory;Edwards, Robert J.;Acharya, Priyamvada
冠状病毒刺突蛋白（S）参与病毒与宿主细胞的融合，是病毒中和的主要免疫原性靶点，也是目前许多疫苗设计工作的重点。具有移动的结构域的高度灵活的S蛋白为免疫系统提供了移动的靶标。在这里，为了更好地了解S蛋白的迁移率，我们对可用的β-CoV S蛋白结构进行了基于结构的载体分析。尽管结构域组织总体相似，但我们发现来自不同β-CoV的S蛋白显示出不同的构型。基于这一分析，我们开发了两个可溶性胞外域结构的SARS-CoV-2 S-蛋白，其中高免疫原性和移动的受体结合结构域（RBD）要么锁定在所有RBD的"向下"的位置或采取"向上"状态构象比野生型S-蛋白更容易。这些结果表明S蛋白的构象可以通过合理的设计来控制，并可以为开发用于疫苗应用的工程化CoV S蛋白提供框架。SARS-CoV-2刺突糖蛋白是柔性的，其受体结合结构域（RBD）在向上或向下构象之间波动。改造到刺突胞外域中的突变要么将RBD锁定在向下状态，要么使其更容易采用向上构象。
The coronavirus (CoV) spike (S) protein, involved in viral-host cell fusion, is the primary immunogenic target for virus neutralization and the current focus of many vaccine design efforts. The highly flexible S-protein, with its mobile domains, presents a moving target to the immune system. Here, to better understand S-protein mobility, we implemented a structure-based vector analysis of available beta-CoV S-protein structures. Despite an overall similarity in domain organization, we found that S-proteins from different beta-CoVs display distinct configurations. Based on this analysis, we developed two soluble ectodomain constructs for the SARS-CoV-2 S-protein, in which the highly immunogenic and mobile receptor binding domain (RBD) is either locked in the all-RBDs 'down' position or adopts 'up' state conformations more readily than the wild-type S-protein. These results demonstrate that the conformation of the S-protein can be controlled via rational design and can provide a framework for the development of engineered CoV S-proteins for vaccine applications.The SARS-CoV-2 spike glycoprotein is flexible, and its receptor-binding domain (RBD) fluctuates between up or down conformations. Mutations engineered into the spike ectodomain either lock the RBD in the down state or make it adopt the up conformation more readily.