Abstract
The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron variant has become the dominant infective strain. We report the structures of the Omicron spike trimer on its own and in complex with angiotensin-converting enzyme 2 (ACE2) or an anti-Omicron antibody. Most Omicron mutations are located on the surface of the spike protein and change binding epitopes to many current antibodies. In the ACE2-binding site, compensating mutations strengthen receptor binding domain (RBD) binding to ACE2. Both the RBD and the apo form of the Omicron spike trimer are thermodynamically unstable. An unusual RBD-RBD interaction in the ACE2-spike complex supports the open conformation and further reinforces ACE2 binding to the spike trimer. A broad-spectrum therapeutic antibody, JMB2002, which has completed a phase 1 clinical trial, maintains neutralizing activity against Omicron. JMB2002 binds to RBD differently from other characterized antibodies and inhibits ACE2 binding.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Angiotensin-Converting Enzyme 2 / chemistry*
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Angiotensin-Converting Enzyme 2 / metabolism
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Antibodies, Neutralizing / chemistry*
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Antibodies, Neutralizing / immunology
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Antibodies, Neutralizing / metabolism
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Antibodies, Neutralizing / therapeutic use
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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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Binding Sites
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Cryoelectron Microscopy
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Epitopes
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Humans
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Immunoglobulin Fab Fragments / chemistry
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Immunoglobulin Fab Fragments / immunology
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Immunoglobulin Fab Fragments / metabolism
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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
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Protein Interaction Domains and Motifs
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Protein Multimerization
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Protein Subunits / chemistry
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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 / metabolism
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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
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Thermodynamics
Substances
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Antibodies, Neutralizing
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Antibodies, Viral
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Epitopes
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Immunoglobulin Fab Fragments
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JMB2002
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Protein Subunits
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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