Department of Biochemistry and Molecular Biology, University of British Columbia, Vancouver, BC V6T 1Z3, Canada.
Department of Biochemistry and Molecular Biology, University of British Columbia, Vancouver, BC V6T 1Z3, Canada; Gandeeva Therapeutics, Inc., Burnaby, BC V5C 6N5, Canada.
Cell Rep. 2023 Jan 31;42(1):111964. doi: 10.1016/j.celrep.2022.111964. Epub 2023 Jan 4.
The BA.2 sub-lineage of the Omicron (B.1.1.529) severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variant rapidly supplanted the original BA.1 sub-lineage in early 2022. Both lineages threatened the efficacy of vaccine-elicited antibodies and acquired increased binding to several mammalian ACE2 receptors. Cryoelectron microscopy (cryo-EM) analysis of the BA.2 spike (S) glycoprotein in complex with mouse ACE2 (mACE2) identifies BA.1- and BA.2-mutated residues Q493R, N501Y, and Y505H as complementing non-conserved residues between human and mouse ACE2, rationalizing the enhanced S protein-mACE2 interaction for Omicron variants. Cryo-EM structures of the BA.2 S-human ACE2 complex and of the extensively mutated BA.2 amino-terminal domain (NTD) reveal a dramatic reorganization of the highly antigenic N1 loop into a β-strand, providing an explanation for decreased binding of the BA.2 S protein to antibodies isolated from BA.1-convalescent patients. Our analysis reveals structural mechanisms underlying the antigenic drift in the rapidly evolving Omicron variant landscape.
奥密克戎（B.1.1.529）的 BA.2 亚谱系迅速取代了 2022 年初的原始 BA.1 亚谱系。这两个谱系都威胁到了疫苗诱导抗体的功效，并增加了对几种哺乳动物 ACE2 受体的结合能力。与小鼠 ACE2（mACE2）结合的 BA.2 刺突（S）糖蛋白的冷冻电镜（cryo-EM）分析确定了 BA.1 和 BA.2 突变残基 Q493R、N501Y 和 Y505H 补充了人类和小鼠 ACE2 之间非保守的残基，合理地解释了奥密克戎变体中 S 蛋白与 ACE2 的增强相互作用。BA.2 S-人 ACE2 复合物和广泛突变的 BA.2 氨基末端结构域（NTD）的 cryo-EM 结构揭示了高度抗原性的 N1 环剧烈重组成 β-链，这为 BA.2 S 蛋白与从 BA.1 康复患者中分离出的抗体结合减少提供了解释。我们的分析揭示了快速进化的奥密克戎变体景观中抗原漂移的结构机制。
