Hitting SARS-CoV-2 in a new spot A key target for therapeutic antibodies against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the spike protein, a trimeric protein complex with each monomer comprising an S1 and an S2 domain that mediate binding to host cells and membrane fusion, respectively. In addition to the receptor binding domain (RBD), S1 has an N-terminal domain (NTD). In searching for neutralizing antibodies, there has been a focus on the RBD. Chi et al. isolated antibodies from 10 convalescent patients and identified an antibody that potently neutralizes the virus but does not bind the RBD. Cryo–electron microscopy revealed the epitope as the NTD. This NTD-targeting antibody may be useful to combine with RBD-targeting antibodies in therapeutic cocktails. Science, this issue p. 650 A region outside of the receptor binding domain of SARS-CoV-2 is targeted by a neutralizing antibody. Developing therapeutics against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) could be guided by the distribution of epitopes, not only on the receptor binding domain (RBD) of the Spike (S) protein but also across the full Spike (S) protein. We isolated and characterized monoclonal antibodies (mAbs) from 10 convalescent COVID-19 patients. Three mAbs showed neutralizing activities against authentic SARS-CoV-2. One mAb, named 4A8, exhibits high neutralization potency against both authentic and pseudotyped SARS-CoV-2 but does not bind the RBD. We defined the epitope of 4A8 as the N-terminal domain (NTD) of the S protein by determining with cryo–eletron microscopy its structure in complex with the S protein to an overall resolution of 3.1 angstroms and local resolution of 3.3 angstroms for the 4A8-NTD interface. This points to the NTD as a promising target for therapeutic mAbs against COVID-19.

中文翻译：

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一种中和人类抗体与 SARS-CoV-2 的 Spike 蛋白的 N 端结构域结合

在新位置击中 SARS-CoV-2 针对严重急性呼吸综合征冠状病毒 2 (SARS-CoV-2) 的治疗性抗体的一个关键目标是刺突蛋白，这是一种三聚体蛋白复合物，每个单体包含一个 S1 和一个 S2 结构域，分别介导与宿主细胞的结合和膜融合。除了受体结合域 (RBD)，S1 还有一个 N 端域 (NTD)。在寻找中和抗体时，一直关注 RBD。Chi 等人 从 10 名康复期患者中分离出抗体，并鉴定出一种抗体，可以有效中和病毒但不结合 RBD。冷冻电子显微镜显示表位为 NTD。这种 NTD 靶向抗体可用于与治疗性鸡尾酒中的 RBD 靶向抗体结合。科学，这个问题 p。650 SARS-CoV-2 受体结合域之外的区域被中和抗体靶向。开发针对严重急性呼吸综合征冠状病毒 2 (SARS-CoV-2) 的疗法可以通过表位的分布来指导，不仅在 Spike (S) 蛋白的受体结合域 (RBD) 上，而且在整个 Spike (S) ） 蛋白质。我们从 10 名康复期 COVID-19 患者中分离并表征了单克隆抗体 (mAb)。三种 mAb 对真正的 SARS-CoV-2 显示出中和活性。一种名为 4A8 的 mAb 对真实和假型 SARS-CoV-2 均表现出高中和效力，但不与 RBD 结合。我们将 4A8 的表位定义为 S 蛋白的 N 端结构域 (NTD)，通过低温电子显微镜确定其与 S 蛋白复合的结构，4A8 的整体分辨率为 3.1 埃，局部分辨率为 3.3 埃-NTD 接口。这表明 NTD 是针对 COVID-19 的治疗性 mAb 的有希望的靶点。