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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.
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Figures
Fig. 1.. High-affinity binding of the SARS-CoV-2…
Fig. 1.. High-affinity binding of the SARS-CoV-2 Omicron spike protein with human ACE2.
( A …
Fig. 1.. High-affinity binding of the SARS-CoV-2 Omicron spike protein with human ACE2. (A) Phylogeny of the SARS-CoV-2 variants. Variants of concern and variants of interest are labeled on the graph, the number of spike protein mutations are positively correlated with the distance from the original strain. (B) Schematic of Omicron spike protein domain architecture. The mutations of Omicron spike protein are labeled with different colors (blue for deleting mutation, red for inserting mutation). Mutations in RBM are compared with wildtype SARS-CoV-2 and four other variants of concern strains. SP, signal peptide; RBD, receptor binding domain; RBM, receptor binding motif; SD1, subdomain 1; SD2, subdomain 2; FP, fusion peptide; HR1, heptad repeat 1; HR2, heptad repeat 2; TM, transmembrane region; CT, cytoplasmic tail. (C and D) Binding of Omicron and WT spike trimer and RBD to ACE2 determined by BLI.
Fig. 2.. The structure of ACE2 bound…
Fig. 2.. The structure of ACE2 bound Omicron spike trimer complex and epitopes of current…
Fig. 2.. The structure of ACE2 bound Omicron spike trimer complex and epitopes of current antibodies. (A) Cryo-EM density of the ACE2-Omicron spike trimer complex. (B) The overall structure of the ACE2-Omicron spike trimer complex and the locations of Omicron mutations. Epitope hotspots are highlighted in red circles with the number of antibodies indicated next to the epitopes. (C) The histogram of epitope corresponding with residue numbers. Each epitope was counted if more than 3 heavy atoms of this residue are closer than 5 Å with the antibody. The PDB IDs and corresponding epitopes were summarized in table S2 in the supplementary materials.
Fig. 3.. Structural analysis of Omicron RBD…
Fig. 3.. Structural analysis of Omicron RBD and ACE2.
( A ) Cryo-EM density of…
Fig. 3.. Structural analysis of Omicron RBD and ACE2. (A) Cryo-EM density of Omicron RBD-RBD-ACE2 interface. ACE2 is colored in orange. The ACE2 bound RBD, also named up RBD is in purple. The down RBD, which directly binds to up RBD is in green. Left panel, a close-up view of RBD-RBD interaction. Middle panel, overall cryo-EM density of down RBD-RBD-ACE2 region. Right panel, the ACE2-RBD binding interface. Residues are shown in sticks with the correspondent cryo-EM density represented in mesh. (B) An overall structural model of Omicron RBD-ACE2 bound region. (C) Zoomed-in view of Omicron RBD-ACE2 with hydrogen bonds interactions. (D) Detailed hydrogen bonds interactions in WT RBD-ACE2 interfaces with the same view as in panel B. WT RBD is sea blue, Omicron RBD is purple, and ACE2 is orange. Hydrogen bond or salt bridge interactions are in dotted lines.
Fig. 4.. Inhibition of ACE2 binding to…
Fig. 4.. Inhibition of ACE2 binding to the spike trimer by an anti-Omicron antibody.
( …
Fig. 4.. Inhibition of ACE2 binding to the spike trimer by an anti-Omicron antibody. (A and C) Binding of JMB2002 Fab to Omicron and WT spike trimer. (B and D) Binding of JMB2002 IgG to Omicron and WT spike trimer. (E) Direct inhibition of ACE2 binding to the Omicron spike trimer by JMB2002. (F) Inhibition of the pseudo virus of Omicron by JMB2002.
Fig. 5.. Structure of Omicron spike trimer…
Fig. 5.. Structure of Omicron spike trimer with antibody JMB2002.
( A ) Cryo-EM density…
Fig. 5.. Structure of Omicron spike trimer with antibody JMB2002. (A) Cryo-EM density map of the Fab-bound Omicron spike trimer showed with two front views. (B) Top view of Fab-bound Omicron spike trimer complex model with fab and nanobody hidden. (C) Superposition of the Fab bound RBD-1 and RBD-2. (D) The structure of the Fab bound RBD-1 and RBD-2. (E) Superposition of the ACE2-bound and Fab-bound RBD-1 shows the Fab binding to RBD-2 inhibits ACE2 binding to RBD-1. (F) Left panel, L452 residue from Omicron RBD interacts with Fab. Right panel, the Delta variant L452R mutation clashes the Fab binding. (G) Binding modes of 4 representative 4 classes of antibody that neutralize SARS-CoV-2. PDB codes: class I, 7CM4; class II, 7CHF; class III, 7K90; class IV, 6WPS. The JMB2002Fab in the Omicron S protein structure shows distinct binding modes from other 4 classes of antibodies. See this image and copyright information in PMC
Comment in
Structural insights into the Omicron spike trimer: tackling the challenges of continuously evolving SARS-CoV-2 variants. Ou J, Wu J, Zhang Q.Ou J, et al.Signal Transduct Target Ther. 2022 Sep 16;7(1):322. doi: 10.1038/s41392-022-01179-5.Signal Transduct Target Ther. 2022.PMID: 36114171Free PMC article.No abstract available.
References
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