Cryo-Electron Microscopy, Bijvoet Center for Biomolecular Research, Department of Chemistry, Faculty of Science, Utrecht University, Padualaan 8, 3584 CH Utrecht, Netherlands.
Virology Section, Infectious Diseases and Immunology Division, Department of Biomolecular Health Sciences, Faculty of Veterinary Medicine, Utrecht University, 3584 CL Utrecht, Netherlands.
Sci Adv. 2021 Jun 2;7(23). doi: 10.1126/sciadv.abf5632. Print 2021 Jun.
The emergence of SARS-CoV-2 antibody escape mutations highlights the urgent need for broadly neutralizing therapeutics. We previously identified a human monoclonal antibody, 47D11, capable of cross-neutralizing SARS-CoV-2 and SARS-CoV and protecting against the associated respiratory disease in an animal model. Here, we report cryo-EM structures of both trimeric spike ectodomains in complex with the 47D11 Fab. 47D11 binds to the closed receptor-binding domain, distal to the ACE2 binding site. The CDRL3 stabilizes the N343 glycan in an upright conformation, exposing a mutationally constrained hydrophobic pocket, into which the CDRH3 loop inserts two aromatic residues. 47D11 stabilizes a partially open conformation of the SARS-CoV-2 spike, suggesting that it could be used effectively in combination with other antibodies targeting the exposed receptor-binding motif. Together, these results reveal a cross-protective epitope on the SARS-CoV-2 spike and provide a structural roadmap for the development of 47D11 as a prophylactic or postexposure therapy for COVID-19.
SARS-CoV-2 抗体逃逸突变的出现凸显了广泛中和治疗药物的迫切需求。我们之前鉴定了一种人源单克隆抗体 47D11，它能够中和 SARS-CoV-2 和 SARS-CoV，并在动物模型中预防相关的呼吸道疾病。在这里，我们报告了与 47D11 Fab 复合物的两种三聚体刺突外域的冷冻电镜结构。47D11 结合到封闭的受体结合域，位于 ACE2 结合位点的远端。CDRL3 稳定 N343 聚糖呈直立构象，暴露出一个受突变限制的疏水性口袋，CDRH3 环插入两个芳香族残基。47D11 稳定了 SARS-CoV-2 刺突的部分开放构象，表明它可以与其他靶向暴露的受体结合基序的抗体有效结合使用。这些结果共同揭示了 SARS-CoV-2 刺突上的一个交叉保护表位，并为 47D11 作为 COVID-19 的预防或暴露后治疗药物的开发提供了结构蓝图。
