Structural analysis of receptor engagement and antigenic drift within the BA.2 spike protein

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 recep-tors. 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 exten-sively mutated BA.2 amino-terminal domain (NTD) reveal a dramatic reorganization of the highly antigenic N1 loop into a b-strand, providing an explanation for decreased binding of the BA.2 S protein to antibodies iso-lated from BA.1-convalescent patients. Our analysis reveals structural mechanisms underlying the antigenic drift in the rapidly evolving Omicron variant landscape.

Automated summary

The BA.2 sub-lineage of the Omicron (B.1.1.529) variant, characterized by mutations in the spike (S) glycoprotein, quickly replaced the original BA.1 sub-lineage in early 2022. These mutations enabled increased binding to ACE2 receptors and posed a threat to vaccine efficacy. Cryo-EM analysis revealed structural changes in the S protein and ACE2 complexes, explaining the enhanced interaction and decreased binding of antibodies from BA.1-convalescent patients to the BA.2 variant. This study provides insights into the structural mechanisms underlying antigenic drift in the rapidly evolving Omicron variant landscape.