The currently circulating Omicron sub-variants are the SARS-CoV-2 strains with the highest number of known mutations. Herein, we found that human angiotensin-converting enzyme 2 (hACE2) binding affinity to the receptor-binding domains (RBDs) of the four early Omicron sub-variants (BA.1, BA.1.1, BA.2, and BA.3) follows the order BA.1.1 > BA.2 > BA.3 ≈ BA.1. The complex structures of hACE2 with RBDs of BA.1.1, BA.2, and BA.3 reveal that the higher hACE2 binding affinity of BA.2 than BA.1 is related to the absence of the G496S mutation in BA.2. The R346K mutation in BA.1.1 majorly affects the interaction network in the BA.1.1 RBD/hACE2 interface through long-range alterations and contributes to the higher hACE2 affinity of the BA.1.1 RBD than the BA.1 RBD. These results reveal the structural basis for the distinct hACE2 binding patterns among BA.1.1, BA.2, and BA.3 RBDs.

目前流行的 Omicron 亚变体是已知突变数量最多的 SARS-CoV-2 毒株。在此，我们发现人血管紧张素转换酶 2 (hACE2) 与四种早期 Omicron 亚变体（BA.1、BA.1.1、BA.2 和 BA.3）的受体结合域 (RBD) 的结合亲和力) 遵循 BA.1.1 > BA.2 > BA.3 ≈ BA.1 的顺序。hACE2 与 BA.1.1、BA.2 和 BA.3 的 RBD 的复杂结构表明，BA.2 的 hACE2 结合亲和力高于 BA.1，这与 BA.2 中不存在 G496S 突变有关。BA.1.1 中的 R346K 突变主要通过远程改变影响 BA.1.1 RBD/hACE2 界面中的相互作用网络，并导致 BA.1.1 RBD 的 hACE2 亲和力高于 BA.1 RBD。