Structural basis of human ACE2 higher binding affinity to currently circulating Omicron SARS-CoV-2 sub-variants BA.2 and BA.1.1.

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. [Display omitted] • Omicron BA.1.1 and BA.2 show higher binding strength to hACE2 than the prototype and BA.1 • Details in the binding interface of BA.1.1, BA.2, and BA.3.RBD with hACE2 are deciphered • R346K in BA.1.1 RBD enhances the interaction with hACE2 through long-range alterations The biochemical and structural analysis of the human angiotensin-converting enzyme-2 (ACE2, the receptor for SARS-CoV-2 viral entry) and the receptor-binding domain (RBD) of four Omicron sub-variants—BA.1, BA.1.1, BA.2, and BA.3—helps to reveal the structural basis of differences in sub-variant binding affinities and the impact of RBD mutations. [ABSTRACT FROM AUTHOR]