The ACE2-binding Interface of SARS-CoV-2 Spike Inherently Deflects Immune Recognition

Hattori, Takamitsu; Noval, María G.; Panchenko, Tatyana; Romero, Larizbeth A.; Teng, Kai Wen; Tada, Takuya; Landau, Nathaniel R.; Stapleford, Kenneth A.; Koide, Shohei

doi:10.1016/j.jmb.2020.166748

Cited by 13 publications

(9 citation statements)

References 37 publications

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“…1D ). This observation was surprising to us because such high prevalence of iso–RBD antibodies in sera has not been reported before, although a couple of studies have shown examples of monoclonal antibodies (mAbs) identified through phage panning from synthetic and alpaca-derived antibody libraries that bind to recombinantly expressed soluble RBD but not to prefusion-stabilized S (91, 92). We considered the possibility that these iso–RBD antibody clonotypes may be low in abundance and were not detected in the eluate of prefusion-stabilized S pulldown due to limitations in the detection sensitivity of Ig-Seq.…”

Section: Resultsmentioning

confidence: 77%

See 1 more Smart Citation

Characterization of SARS-CoV-2 Convalescent Patients’ Serological Repertoire Reveals High Prevalence of Iso–RBD Antibodies

Curtis,

Shin,

Hederman

et al. 2023

Preprint

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While our understanding of SARS-CoV-2 pathogenesis and antibody responses following infection and vaccination has improved tremendously since the outbreak in 2019, the sequence identities and relative abundances of the individual constituent antibody molecules in circulation remain understudied. Using Ig-Seq, we proteomically profiled the serological repertoire specific to the whole ectodomain of SARS-CoV-2 prefusion-stabilized spike (S) as well as to the receptor binding domain (RBD) over a 6-month period in four subjects following SARS-CoV-2 infection before SARS-CoV-2 vaccines were available. In each individual, we identified between 59 and 167 unique IgG clonotypes in serum. To our surprise, we discovered that ∼50% of serum IgG specific for RBD did not recognize prefusion-stabilized S (referred to as iso–RBD antibodies), suggesting that a significant fraction of serum IgG targets epitopes on RBD inaccessible on the prefusion-stabilized conformation of S. On the other hand, the abundance of iso–RBD antibodies in nine individuals who received mRNA-based COVID-19 vaccines encoding prefusion-stabilized S was significantly lower (∼8%). We expressed a panel of 12 monoclonal antibodies (mAbs) that were abundantly present in serum from two SARS-CoV-2 infected individuals, and their binding specificities to prefusion-stabilized S and RBD were all in agreement with the binding specificities assigned based on the proteomics data, including 1 iso–RBD mAb which bound to RBD but not to prefusion-stabilized S. 2 of 12 mAbs demonstrated neutralizing activity, while other mAbs were non-neutralizing. 11 of 12 mAbs also bound to S (B.1.351), but only 1 maintained binding to S (B.1.1.529). This particular mAb binding to S (B.1.1.529) 1) represented an antibody lineage that comprised 43% of the individual’s total S-reactive serum IgG binding titer 6 months post-infection, 2) bound to the S from a related human coronavirus, HKU1, and 3) had a high somatic hypermutation level (10.9%), suggesting that this antibody lineage likely had been elicited previously by pre-pandemic coronavirus and was re-activated following the SARS-CoV-2 infection. All 12 mAbs demonstrated their ability to engage in Fc-mediated effector function activities. Collectively, our study provides a quantitative overview of the serological repertoire following SARS-CoV-2 infection and the significant contribution of iso–RBD antibodies, demonstrating how vaccination strategies involving prefusion-stabilized S may have reduced the elicitation of iso–RBD serum antibodies which are unlikely to contribute to protection.

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Section: Resultsmentioning

confidence: 77%

“…Iso–RBD antibodies have been sparsely observed in peripheral B cell analysis (91, 92, 113) and have not been documented in serological analyses. For the first time, we demonstrate the high prevalence of iso–RBD antibodies in serum following infection compared to the infection-naïve, vaccinated group ( Fig.…”

Section: Discussionmentioning

confidence: 99%

Characterization of SARS-CoV-2 Convalescent Patients’ Serological Repertoire Reveals High Prevalence of Iso–RBD Antibodies

Curtis,

Shin,

Hederman

et al. 2023

Preprint

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“…The spike protein is located on the surface of the SARS-CoV-2 virus and its molecular interaction with ACE2 plays a major role in viral entry into host cells (Hattori et al, 2021 ). Therefore, understanding the conformational effects of receptor binding domain (RBD) amino acid substitutions that occur at this interface, which could increase the infectivity of the virus, has important implications for vaccine- or drug-based treatment strategies.…”

Section: Resultsmentioning

confidence: 99%

Understanding the molecular interaction of SARS-CoV-2 spike mutants with ACE2 (angiotensin converting enzyme 2)

İstifli

Netz

Tepe

et al. 2021

Journal of Biomolecular Structure and Dynamics

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Covid-19 is a viral disease caused by the virus SARS-CoV-2 that spread worldwide and caused more than 4.3 million deaths. Moreover, SARS-CoV-2 still continues to evolve, and specifically the E484K, N501Y, and South Africa triple (K417N + E484K + N501Y) spike protein mutants remain as the ‘escape’ phenotypes. The aim of this study was to compare the interaction between the receptor binding domain (RBD) of the E484K, N501Y and South Africa triple spike variants and ACE2 with the interaction between wild-type spike RBD-ACE2 and to show whether the obtained binding affinities and conformations corraborate clinical findings. The structures of the RBDs of the E484K, N501Y and South Africa triple variants were generated with DS Studio v16 and energetically minimized using the CHARMM22 force field. Protein-protein dockings were performed in the HADDOCK server and the obtained wild-type and mutant spike-ACE2 complexes were submitted to 200-ns molecular dynamics simulations with subsequent free energy calculations using GROMACS. Based on docking binding affinities and free energy calculations the E484K, N501Y and triple mutant variants were found to interact stronger with the ACE2 than the wild-type spike. Interestingly, molecular dynamics and MM-PBSA results showed that E484K and spike triple mutant complexes were more stable than the N501Y one. Moreover, the E484K and South Africa triple mutants triggered greater conformational changes in the spike glycoprotein than N501Y. The E484K variant alone, or the combination of K417N + E484K + N501Y mutations induce significant conformational transitions in the spike glycoprotein, while increasing the spike-ACE2 binding affinity. Communicated by Ramaswamy H. Sarma

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“…Compared to the omicron structure, in α-coronavirus spike protein, there is a reduction in α helix in NTD and RBD domain, while in β-coronavirus, in RBD less α helix are present, γ structure is similar, but δ RBD consist earlier omicron strain. Earlier research signifies the importance of protein-protein interaction as spike protein molecular interaction with hACE2 for the access of the virus into the host cell [ 47 ]. The substitution in amino acids present in the spike protein RBD domain in different strains from α, β, γ, δ, and Omicron due to mutation increases the transmissibility and infectivity of the virus.…”

Section: Discussionmentioning

confidence: 99%

Proteomic Approach for Comparative Analysis of the Spike Protein of SARS-CoV-2 Omicron (B.1.1.529) Variant and Other Pango Lineages

et al. 2022

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The novel SARS-CoV-2 variant, Omicron (B.1.1.529), is being testified, and the WHO has characterized Omicron as a variant of concern due to its higher transmissibility and very contagious behavior, immunization breakthrough cases. Here, the comparative proteomic study has been conducted on spike-protein, hACE2 of five lineages (α, β, δ, γ and Omicron. The docking was performed on spike protein- hACE-2 protein using HADDOCK, and PRODIGY was used to analyze the binding energy affinity using a reduced Haddock score. Followed by superimposition in different variant-based protein structures and calculated the esteem root mean square deviation (RMSD). This study reveals that Omicron was seen generating a monophyletic clade. Further, as α variant is the principal advanced strain after Wuhan SARS-CoV-2, and that is the reason it was showing the least likeness rate with the Omicron and connoting Omicron has developed of late with the extreme number of mutations. α variant has shown the highest binding affinity with hACE2, followed by β strain, and followed with γ. Omicron showed a penultimate binding relationship, while the δ variant was seen as having the least binding affinity. This proteomic basis in silico analysis of variable spike proteins of variants will impart light on the development of vaccines and the identification of mutations occurring in the upcoming variants.

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The ACE2-binding Interface of SARS-CoV-2 Spike Inherently Deflects Immune Recognition

Cited by 13 publications

References 37 publications

Characterization of SARS-CoV-2 Convalescent Patients’ Serological Repertoire Reveals High Prevalence of Iso–RBD Antibodies

Characterization of SARS-CoV-2 Convalescent Patients’ Serological Repertoire Reveals High Prevalence of Iso–RBD Antibodies

Understanding the molecular interaction of SARS-CoV-2 spike mutants with ACE2 (angiotensin converting enzyme 2)

Proteomic Approach for Comparative Analysis of the Spike Protein of SARS-CoV-2 Omicron (B.1.1.529) Variant and Other Pango Lineages

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