biostudies-literatureMcCallum MNIAID NIH HHSWellcome TrustNIGMS NIH HHSNIH HHS864-868https://www.ebi.ac.uk/biostudies/studies/S-EPMC9427005biostudies-literatureUnknown375(6583)The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron variant of concern evades antibody-mediated immunity that comes from vaccination or infection with earlier variants due to accumulation of numerous spike mutations. To understand the Omicron antigenic shift, we determined cryo-electron microscopy and x-ray crystal structures of the spike protein and the receptor-binding domain bound to the broadly neutralizing sarbecovirus monoclonal antibody (mAb) S309 (the parent mAb of sotrovimab) and to the human ACE2 receptor. We provide a blueprint for understanding the marked reduction of binding of other therapeutic mAbs that leads to dampened neutralizing activity. Remodeling of interactions between the Omicron receptor-binding domain and human ACE2 likely explains the enhanced affinity for the host receptor relative to the ancestral virus.Science (New York, N.Y.)Structural basis of SARS-CoV-2 Omicron immune evasion and receptor engagement.PMC9427005S10 OD023476DP1 AI158186HHSN272201700059CT32 GM008268P30 GM124169R01 GM120553209407/Z/17/ZVeesler DRosen LEJoshi AWalls ACDillen JRSnell GPowell AEHauser KMcCallum MCzudnochowski NCroll TICorti DStewart CBowen JENix JZepeda SKVirgin HWfalseStructural basis of SARS-CoV-2 Omicron immune evasion and receptor engagement.The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron variant of concern evades antibody-mediated immunity that comes from vaccination or infection with earlier variants due to accumulation of numerous spike mutations. To understand the Omicron antigenic shift, we determined cryo-electron microscopy and x-ray crystal structures of the spike protein and the receptor-binding domain bound to the broadly neutralizing sarbecovirus monoclonal antibody (mAb) S309 (the parent mAb of sotrovimab) and to the human ACE2 receptor. We provide a blueprint for understanding the marked reduction of binding of other therapeutic mAbs that leads to dampened neutralizing activity. Remodeling of interactions between the Omicron receptor-binding domain and human ACE2 likely explains the enhanced affinity for the host receptor relative to the ancestral virus.2022-01-01T00:00:00Z2022 Feb2026-05-27T23:24:06.959Z2026-04-08T01:59:39.217ZS-EPMC94270053507625610.1126/science.abn8652