Center for Infectious Disease Research, Westlake Laboratory of Life Sciences and Biomedicine, Key Laboratory of Structural Biology of Zhejiang Province, School of Life Sciences, Westlake University, Hangzhou 310024, China.
Beijing Advanced Innovation Center for Structural Biology, Tsinghua-Peking Joint Center for Life Sciences, School of Life Sciences, Tsinghua University, Beijing 100084, China.
Viruses. 2023 Jun 20;15(6):1398. doi: 10.3390/v15061398.
The Omicron variants of SARS-CoV-2 have emerged as the dominant strains worldwide, causing the COVID-19 pandemic. Each Omicron subvariant contains at least 30 mutations on the spike protein (S protein) compared to the original wild-type (WT) strain. Here we report the cryo-EM structures of the trimeric S proteins from the BA.1, BA.2, BA.3, and BA.4/BA.5 subvariants, with BA.4 and BA.5 sharing the same S protein mutations, each in complex with the surface receptor ACE2. All three receptor-binding domains of the S protein from BA.2 and BA.4/BA.5 are "up", while the BA.1 S protein has two "up" and one "down". The BA.3 S protein displays increased heterogeneity, with the majority in the all "up" RBD state. The different conformations preferences of the S protein are consistent with their varied transmissibility. By analyzing the position of the glycan modification on Asn343, which is located at the S309 epitopes, we have uncovered the underlying immune evasion mechanism of the Omicron subvariants. Our findings provide a molecular basis of high infectivity and immune evasion of Omicron subvariants, thereby offering insights into potential therapeutic interventions against SARS-CoV-2 variants.
新冠病毒（SARS-CoV-2）的奥密克戎变体已成为全球主要流行株，引发了 COVID-19 大流行。与原始野生型（WT）株相比，每种奥密克戎亚变体的刺突蛋白（S 蛋白）上至少含有 30 个突变。在这里，我们报告了 BA.1、BA.2、BA.3 和 BA.4/BA.5 亚变体的三聚体 S 蛋白的冷冻电镜结构，其中 BA.4 和 BA.5 具有相同的 S 蛋白突变，分别与表面受体 ACE2 复合物。BA.2 和 BA.4/BA.5 的 S 蛋白的三个受体结合结构域均“朝上”，而 BA.1 的 S 蛋白有两个“朝上”和一个“朝下”。BA.3 的 S 蛋白显示出更高的异质性，大多数处于全“朝上”RBD 状态。S 蛋白的不同构象偏好与其不同的传染性一致。通过分析位于 S309 表位的 Asn343 上糖基化修饰的位置，我们揭示了奥密克戎亚变体的免疫逃逸机制。我们的研究结果为奥密克戎亚变体的高传染性和免疫逃逸提供了分子基础，从而为针对 SARS-CoV-2 变体的潜在治疗干预提供了思路。
