Deep Mutational Scanning of SARS-CoV-2 Receptor Binding Domain Reveals Constraints on Folding and ACE2 Binding
Deep Mutational Scanning of SARS-CoV-2 Receptor Binding Domain Reveals Constraints on Folding and ACE2 Binding
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DOI：
10.1016/j.cell.2020.08.012
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发表时间：
2020-09-03
期刊：
影响因子：
64.5
通讯作者：
Bloom, Jesse D.
中科院分区：
文献类型：
--
作者：
Starr, Tyler N.;Greaney, Allison J.;Bloom, Jesse D.
SARS-CoV-2刺突糖蛋白的受体结合域(RBD)介导病毒与ACE2受体的结合，是宿主范围的主要决定因素和中和抗体的主要靶点。在这里，我们实验测量了RBD的所有氨基酸突变如何影响折叠蛋白的表达及其与ACE2的亲和力。大多数突变对RBD的表达和ACE2结合都是有害的，我们确定了RBD表面的受限区域，这些区域可能是疫苗和基于抗体的治疗的理想靶点。但相当数量的突变是耐受性很好的，甚至增强了ACE2的结合，包括ACE2界面残基，这种残基在SARS相关冠状病毒中存在差异。然而，我们没有发现证据表明在目前的SARS-CoV-2大流行分离株中选择了这些ACE2亲和力增强的突变。我们提出了一种交互式可视化和开放式分析管道，以促进将我们的数据集用于疫苗设计和在病毒监测期间观察到的突变的功能注释。
The receptor binding domain (RBD) of the SARS-CoV-2 spike glycoprotein mediates viral attachment to ACE2 receptor and is a major determinant of host range and a dominant target of neutralizing antibodies. Here, we experimentally measure how all amino acid mutations to the RBD affect expression of folded protein and its affinity for ACE2. Most mutations are deleterious for RBD expression and ACE2 binding, and we identify constrained regions on the RBD's surface that may be desirable targets for vaccines and antibody-based therapeutics. But a substantial number of mutations are well tolerated or even enhance ACE2 binding, including at ACE2 interface residues that vary across SARS-related coronaviruses. However, we find no evidence that these ACE2-affinity-enhancing mutations have been selected in current SARS-CoV-2 pandemic isolates. We present an interactive visualization and open analysis pipeline to facilitate use of our dataset for vaccine design and functional annotation of mutations observed during viral surveillance.