Structural analysis of receptor binding domain mutations in SARS-CoV-2 variants of concern that modulate ACE2 and antibody binding

Mannar, Dhiraj; Saville, James W.; Zhu, Xing; Srivastava, Shanti Swaroop; Berezuk, Alison; Zhou, Shaoyu; Tuttle, K.S.; Kim, Andrew; Li, Wei; Dimitrov, Dimiter S.; Subramaniam, Sriram

doi:10.1016/j.celrep.2021.110156

Cited by 73 publications

(95 citation statements)

References 66 publications

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“…3D). Additionally, the mutated residue Y501 in the Omicron RBD makes pi stacking interactions with Y41 in ACE2 as previously seen in the Alpha (B.1.1.7), Beta (B.1.351), and Gamma (P.1) variants (8,12), while mutated residue H505 is not hydrogen-bonded to E37 in ACE2 in contrast to what we reported previously for the Y505 residue (Fig. 3E) (20).…”

supporting

confidence: 64%

SARS-CoV-2 Omicron variant: Antibody evasion and cryo-EM structure of spike protein–ACE2 complex

Mannar

Saville

Zhu

et al. 2022

Science

Self Cite

565

638

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The newly reported Omicron variant is poised to replace Delta as the most prevalent SARS-CoV-2 variant across the world. Cryo-EM structural analysis of the Omicron variant spike protein in complex with human ACE2 reveals new salt bridges and hydrogen bonds formed by mutated residues R493, S496 and R498 in the RBD with ACE2. These interactions appear to compensate for other Omicron mutations such as K417N known to reduce ACE2 binding affinity, resulting in similar biochemical ACE2 binding affinities for Delta and Omicron variants. Neutralization assays show that pseudoviruses displaying the Omicron spike protein exhibit increased antibody evasion. The increase in antibody evasion, together with retention of strong interactions at the ACE2 interface, thus represent important molecular features that likely contribute to the rapid spread of the Omicron variant.

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supporting

confidence: 64%

SARS-CoV-2 Omicron variant: Antibody evasion and cryo-EM structure of spike protein–ACE2 complex

Mannar

Saville

Zhu

et al. 2022

Science

Self Cite

565

638

View full text Add to dashboard Cite

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“…5C ). Coincidentally, residues Y453, A475, Y489, R493, T500, Y501, and H505 of the Omicron RBD are important for ACE2 recognition and binding 14 . The neutralization activity test showed that 16L9 alone was able to broadly neutralize SARS-CoV-2 and SARS-CoV-2 variants.…”

Section: Resultsmentioning

confidence: 99%

Combating the SARS-CoV-2 Omicron variant with non-Omicron neutralizing antibodies

Wang

Zhang

Liu

et al. 2022

Preprint

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The highly mutated and transmissible Omicron variant has provoked serious concerns over its decreased sensitivity to the current coronavirus disease 2019 (COVID-19) vaccines and evasion from most anti-severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) neutralizing antibodies (NAbs). In this study, we explored the possibility of combatting the Omicron variant by constructing bispecific antibodies based on non-Omicron NAbs. We engineered ten IgG-like bispecific antibodies with non-Omicron NAbs named GW01, 16L9, 4L12, and REGN10987 by fusing the single-chain variable fragments (scFvs) of two antibodies through a linker and then connecting them to the Fc region of IgG1. Surprisingly, eight out of ten bispecific antibodies showed high binding affinity to the Omicron receptor-binding domain (RBD) and exhibited extreme breadth and potency against pseudotyped SARS-CoV-2 variants of concern (VOCs) including Omicron, as well as authentic Omicron(+R346K) variants. Six bispecific antibodies containing the cross-NAb GW01 neutralized Omicron variant and retained their abilities to neutralize other sarbecoviruses. Bispecific antibodies inhibited Omicron infection by binding to the ACE2 binding site. A cryo-electron microscopy (cryo-EM) structure study of the representative bispecific antibody FD01 in complex with the Omicron spike (S) revealed 5 distinct trimers and one unique bi-trimer conformation. The structure and mapping analyses of 34 Omicron S variant single mutants elucidated that two scFvs of the bispecific antibody synergistically induced the RBD-down conformation into 3-RBD-up conformation, enlarged the interface area, accommodated the S371L mutation, improved the affinity between a single IgG and the Omicron RBD, and hindered ACE2 binding by forming bi-trimer conformation. Our study offers an important foundation for anti-Omicron NAb design. Engineering bispecific antibodies based on non-Omicron NAbs may provide an efficient solution to combat the Omicron variant.

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“…For the 17 residues in RBD interfaces with Angiotensin-Converting Enzyme 2 (ACE2) 5 , eight were mutated in the different variants. In detail, K417N was observed in the Omicron, Beta and Gamma variants, which reduces ACE2 binding significantly 6,7 . Whereas N501Y, which exhibit increased ACE2 binding affinity 8,9 , was detected in all other 6 variants except Delta and Lambda.…”

mentioning

confidence: 95%

Spike mutations of the SARS-CoV-2 Omicron: more likely to occur in the epitopes

Chen

Liu

et al. 2022

Preprint

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Almost two years since the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) outbreak in 2019, and it is still pandemic over the world. SARS-COV-2 continuing to mutate and evolve, which further exacerbated the spread of the epidemic. Omicron variant, as an emerging mutation recently in South Africa, spreaded fastly to other countries worldwide. However, the gene charicterstic of Omicron and the effect on epitopes are still unclear. In this study, we retrieved 800 SARS-CoV-2 full-length sequences from GISAID database on 14 December 2021 (Alpha 110, Beta 101, Gamma 108, Delta 110, Omicron 107, Lambda 98, Mu 101, GH/490R 65). Overall, 1320 amino acid (AA) sites were mutated in these 800 SARS-CoV-2 sequences. Covariant network analysis showed that the covariant network of Omicron variant was significantly different from other variants. Further, 218 of the 1320 AA sites were occurred in the S gene, including 78 high-frequency mutations (>90%). Notably, we identified 25 unique AA mutations in Omicron, which may affect the transmission and pathogenicity of SARS-CoV-2. Finally, we analyzed the effect of Omicron on epitope peptide. As expected, 64.1% mutations (25/39) of Omicron variants were in epitopes, which was significantly higher than in other variants. These mutations may cause a poor response to vaccines to Omicron variants. In conclusion, Omicron variants, as an emerging mutation, should be alerted for us due that it may lead to poor vaccine response, and more data is needed to evaluate the virulence and vaccines responses to this variants.

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Structural analysis of receptor binding domain mutations in SARS-CoV-2 variants of concern that modulate ACE2 and antibody binding

Cited by 73 publications

References 66 publications

SARS-CoV-2 Omicron variant: Antibody evasion and cryo-EM structure of spike protein–ACE2 complex

SARS-CoV-2 Omicron variant: Antibody evasion and cryo-EM structure of spike protein–ACE2 complex

Combating the SARS-CoV-2 Omicron variant with non-Omicron neutralizing antibodies

Spike mutations of the SARS-CoV-2 Omicron: more likely to occur in the epitopes

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