Cross-Neutralization of a SARS-CoV-2 Antibody to a Functionally Conserved Site Is Mediated by Avidity.
Cross-Neutralization of a SARS-CoV-2 Antibody to a Functionally Conserved Site Is Mediated by Avidity.
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DOI：
10.1101/2020.08.02.233536
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发表时间：
2020-12-15
期刊：
影响因子：
32.4
通讯作者：
Wilson, Ian A
中科院分区：
文献类型：
--
作者：
Liu, Hejun;Wu, Nicholas C;Wilson, Ian A
从COVID-19患者中分离的大多数抗体对SARS-CoV-2具有特异性。COVA1-16是一种相对罕见的抗体，也能交叉中和SARS-CoV。在这里，我们用SARS-CoV-2 RBD测定了cova1 - 16fab的晶体结构，并用刺突糖蛋白三聚体进行了负染色电镜重建，以阐明其交叉反应性的结构基础。COVA1-16主要通过长CDR H3结合SARS-CoV-2 RBD上高度保守的表位，并由于位阻而不是表位重叠而与ACE2结合竞争。COVA1-16与刺突上RBD的一个灵活的向上构象结合，并依赖于抗体的亲和力来中和。这些发现，以及表位保护的结构和功能原理，为开发更通用的sars样冠状病毒疫苗和疗法提供了蓝图。从2019冠状病毒病（COVID-19）患者中分离的大多数抗体对严重急性呼吸综合征冠状病毒2 （SARS-CoV-2）具有特异性。然而，COVA1-16是一种相对罕见的抗体，也能交叉中和SARS-CoV。在这里，我们确定了COVA1-16抗体片段（Fab）与SARS-CoV-2受体结合域（RBD）的晶体结构，并用刺突糖蛋白三聚体进行负染色电镜重建，以阐明其交叉反应性的结构基础。COVA1-16主要通过长互补决定区（CDR） H3结合SARS-CoV-2 RBD上高度保守的表位，并由于空间位阻而不是表位重叠而与血管紧张素转换酶2 （ACE2）受体竞争。COVA1-16与刺突上RBD的一个灵活的向上构象结合，并依赖于抗体的亲和力来中和。这些发现，以及表位保护的结构和功能原理，为开发更通用的类sars冠状病毒疫苗和疗法提供了见解。
Most antibodies isolated from COVID-19 patients are specific to SARS-CoV-2. COVA1-16 is a relatively rare antibody that also cross-neutralizes SARS-CoV. Here we determined a crystal structure of COVA1-16 Fab with the SARS-CoV-2 RBD, and a negative-stain EM reconstruction with the spike glycoprotein trimer, to elucidate the structural basis of its cross-reactivity. COVA1-16 binds a highly conserved epitope on the SARS-CoV-2 RBD, mainly through a long CDR H3, and competes with ACE2 binding due to steric hindrance rather than epitope overlap. COVA1-16 binds to a flexible up conformation of the RBD on the spike and relies on antibody avidity for neutralization. These findings, along with structural and functional rationale for the epitope conservation, provide a blueprint for development of more universal SARS-like coronavirus vaccines and therapies.Most antibodies isolated from individuals with coronavirus disease 2019 (COVID-19) are specific to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). However, COVA1-16 is a relatively rare antibody that also cross-neutralizes SARS-CoV. Here, we determined a crystal structure of the COVA1-16 antibody fragment (Fab) with the SARS-CoV-2 receptor-binding domain (RBD) and negative-stain electron microscopy reconstructions with the spike glycoprotein trimer to elucidate the structural basis of its cross-reactivity. COVA1-16 binds a highly conserved epitope on the SARS-CoV-2 RBD, mainly through a long complementarity-determining region (CDR) H3, and competes with the angiotensin-converting enzyme 2 (ACE2) receptor because of steric hindrance rather than epitope overlap. COVA1-16 binds to a flexible up conformation of the RBD on the spike and relies on antibody avidity for neutralization. These findings, along with the structural and functional rationale for epitope conservation, provide insights for development of more universal SARS-like coronavirus vaccines and therapies.