Potent neutralizing SARS-CoV-2 antibodies often target the spike protein receptor-binding site (RBS), but the variability of RBS epitopes hampers broad neutralization of multiple sarbecoviruses and drifted viruses. Here, using humanized mice, we identified an RBS antibody with a germline V_H gene that potently neutralized SARS-related coronaviruses, including SARS-CoV and SARS-CoV-2 variants. X-ray crystallography revealed coordinated recognition by the heavy chain of non-RBS conserved sites and the light chain of RBS with a binding angle mimicking the angiotensin-converting enzyme 2 (ACE2) receptor. The minimum footprints in the hypervariable region of RBS contributed to the breadth of neutralization, which was enhanced by immunoglobulin G3 (IgG3) class switching. The coordinated binding resulted in broad neutralization of SARS-CoV and emerging SARS-CoV-2 variants of concern. Low-dose therapeutic antibody treatment in hamsters reduced the virus titers and morbidity during SARS-CoV-2 challenge. The structural basis for broad neutralizing activity may inform the design of a broad spectrum of therapeutics and vaccines.

有效的中和 SARS-CoV-2 抗体通常靶向刺突蛋白受体结合位点 (RBS)，但 RBS 表位的可变性阻碍了对多种 sarbecovirus 和漂移病毒的广泛中和。在这里，我们使用人源化小鼠鉴定了一种具有种系 VH 的 RBS_抗体有效中和 SARS 相关冠状病毒（包括 SARS-CoV 和 SARS-CoV-2 变体）的基因。X 射线晶体学揭示了非 RBS 保守位点的重链和 RBS 轻链的协调识别，其结合角模仿血管紧张素转换酶 2 (ACE2) 受体。RBS 高变区的最小足迹有助于中和的广度，免疫球蛋白 G3 (IgG3) 类别转换增强了中和的广度。协同结合导致 SARS-CoV 和新出现的令人担忧的 SARS-CoV-2 变体的广泛中和。仓鼠的低剂量治疗性抗体治疗降低了 SARS-CoV-2 攻击期间的病毒滴度和发病率。广泛中和活性的结构基础可以为广谱疗法和疫苗的设计提供信息。