Structural and functional impact by SARS-CoV-2 Omicron spike mutations

The Omicron variant of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), bearing an unusually high number of mutations, has become a dominant strain in many countries within several weeks. We report here structural, functional, and antigenic properties of its full-length spike (S) protein with a native sequence in comparison with those of previously prevalent variants. Omicron S requires a substantially higher level of host receptor ACE2 for efficient membrane fusion than other variants, possibly explaining its unexpected cellular tropism. Mutations not only remodel the antigenic structure of the N-terminal domain of the S protein but also alter the surface of the receptor-binding domain in a way not seen in other variants, consistent with its remarkable resistance to neutralizing antibodies. These results suggest that Omicron S has acquired an extraordinary ability to evade host immunity by excessive mutations, which also compromise its fusogenic capability. [Display omitted] •Omicron spike requires a high level of ACE2 for efficient membrane fusion•Mutations in Omicron remodel the antigenic surfaces of the spike trimer•Excessive mutations may have compromised fusogenic capability of Omicron spike Zhang et al. report that SARS-CoV-2 Omicron variant has an unusually high number of mutations in its spike (S), which requires a high level of host receptor ACE2 for efficient membrane fusion, thereby compromising its fusogenic capability. Mutations remodel the S antigenic structure, causing remarkable resistance to neutralizing antibodies.