Department of Biochemistry and Molecular Biology, University of British Columbia, Vancouver, BC, V6T 1Z3, Canada.
Center for Antibody Therapeutics, Division of Infectious Diseases, Department of Medicine, University of Pittsburgh School of Medicine, 3550 Terrace Street, Pittsburgh, PA, 15261, USA.
Nat Commun. 2022 Aug 18;13(1):4696. doi: 10.1038/s41467-022-32262-8.
Mutations in the spike glycoproteins of SARS-CoV-2 variants of concern have independently been shown to enhance aspects of spike protein fitness. Here, we describe an antibody fragment (V ab6) that neutralizes all major variants including the recently emerged BA.1 and BA.2 Omicron subvariants, with a unique mode of binding revealed by cryo-EM studies. Further, we provide a comparative analysis of the mutational effects within previously emerged variant spikes and identify the structural role of mutations within the NTD and RBD in evading antibody neutralization. Our analysis shows that the highly mutated Gamma N-terminal domain exhibits considerable structural rearrangements, partially explaining its decreased neutralization by convalescent sera. Our results provide mechanistic insights into the structural, functional, and antigenic consequences of SARS-CoV-2 spike mutations and highlight a spike protein vulnerability that may be exploited to achieve broad protection against circulating variants.
刺突糖蛋白中的突变已被独立证明可增强刺突蛋白适应性的各个方面。在这里，我们描述了一种抗体片段（V ab6），该片段可中和所有主要变体，包括最近出现的 BA.1 和 BA.2 奥密克戎亚变体，通过冷冻电镜研究揭示了独特的结合模式。此外，我们还对先前出现的变体刺突中的突变效应进行了比较分析，并确定了 NTD 和 RBD 内突变在逃避抗体中和中的结构作用。我们的分析表明，高度突变的伽马 N 端结构域表现出相当大的结构重排，部分解释了其被恢复期血清中和的能力降低。我们的研究结果为 SARS-CoV-2 刺突突变的结构、功能和抗原性后果提供了机制见解，并突出了刺突蛋白的脆弱性，这可能被利用来实现对循环变体的广泛保护。
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