Abstract
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.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, Non-P.H.S.
MeSH terms
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Amino Acid Substitution
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Angiotensin-Converting Enzyme 2 / chemistry*
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Angiotensin-Converting Enzyme 2 / metabolism
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Antibodies, Monoclonal / chemistry
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Antibodies, Monoclonal / immunology
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Antibodies, Monoclonal / metabolism
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Antibodies, Viral / chemistry*
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Antibodies, Viral / immunology
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Antibodies, Viral / metabolism
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Antigenic Drift and Shift
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Broadly Neutralizing Antibodies / chemistry
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Broadly Neutralizing Antibodies / immunology
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Broadly Neutralizing Antibodies / metabolism
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Cryoelectron Microscopy
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Crystallography, X-Ray
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Humans
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Immune Evasion*
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Models, Molecular
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Mutation
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Protein Binding
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Protein Conformation
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Protein Domains / genetics
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Protein Interaction Domains and Motifs / genetics
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Receptors, Coronavirus / chemistry*
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Receptors, Coronavirus / metabolism
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SARS-CoV-2 / chemistry*
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SARS-CoV-2 / genetics
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SARS-CoV-2 / immunology*
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SARS-CoV-2 / physiology
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Spike Glycoprotein, Coronavirus / chemistry*
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Spike Glycoprotein, Coronavirus / genetics
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Spike Glycoprotein, Coronavirus / immunology
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Spike Glycoprotein, Coronavirus / metabolism
Substances
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Antibodies, Monoclonal
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Antibodies, Viral
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Broadly Neutralizing Antibodies
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Receptors, Coronavirus
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Spike Glycoprotein, Coronavirus
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spike protein, SARS-CoV-2
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ACE2 protein, human
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Angiotensin-Converting Enzyme 2