The effect of the D614G substitution on the structure of the spike glycoprotein of SARS-CoV-2

Benton, D.J.; Wrobel, Antoni G.; Roustan, Chloë; Borg, Annabel; Xu, Pengqi; Martin, Stephen R.; Rosenthal, Peter B.; Skehel, J.J.; Gamblin, S.J.

doi:10.1073/pnas.2022586118

Cited by 144 publications

(201 citation statements)

References 31 publications

(47 reference statements)

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“…These various mutations may provide an avenue for the SARS-CoV-2 to escape from immunity of the current vaccine against COVID19. Because of this, recent SARS-CoV-2 variant B.1.351, particularly those with mutations in the RBM of spike that potentially bring about conformational changes to the spike protein, got attention [1,17,19]. Herein, we show that K417N and E484K spike mutations derived from SARS-CoV-2 B.1.351 variant has a greater affinity for ACE2 as compared to the D614G derived from SARS-CoV-2 Wuhan variant via MD simulation-based predictions (Table 1 and Figure 2).…”

Section: Resultsmentioning

confidence: 99%

The Impact on Infectivity and Neutralization Efficiency of SARS-CoV-2 Lineage B.1.351 Pseudovirus

Kim

Jang

Soh

et al. 2021

Viruses

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A new variant of SARS-CoV-2 B.1.351 lineage (first found in South Africa) has been raising global concern due to its harboring of multiple mutations in the spike that potentially increase transmissibility and yield resistance to neutralizing antibodies. We here tested infectivity and neutralization efficiency of SARS-CoV-2 spike pseudoviruses bearing particular mutations of the receptor-binding domain (RBD) derived either from the Wuhan strains (referred to as D614G or with other sites) or the B.1.351 lineage (referred to as N501Y, K417N, and E484K). The three different pseudoviruses B.1.351 lineage related significantly increased infectivity compared with other mutants that indicated Wuhan strains. Interestingly, K417N and E484K mutations dramatically enhanced cell–cell fusion than N501Y even though their infectivity were similar, suggesting that K417N and E484K mutations harboring SARS-CoV-2 variant might be more transmissible than N501Y mutation containing SARS-CoV-2 variant. We also investigated the efficacy of two different monoclonal antibodies, Casirivimab and Imdevimab that neutralized SARS-CoV-2, against several kinds of pseudoviruses which indicated Wuhan or B.1.351 lineage. Remarkably, Imdevimab effectively neutralized B.1.351 lineage pseudoviruses containing N501Y, K417N, and E484K mutations, while Casirivimab partially affected them. Overall, our results underscore the importance of B.1.351 lineage SARS-CoV-2 in the viral spread and its implication for antibody efficacy.

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Section: Resultsmentioning

confidence: 99%

The Impact on Infectivity and Neutralization Efficiency of SARS-CoV-2 Lineage B.1.351 Pseudovirus

Kim

Jang

Soh

et al. 2021

Viruses

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“…A similar behavior is seen with the wild-type sequence (D614), which has lower neutralization than G614 even if no other difference is present; a plausible explanation is that G614 makes the CoV-X2 epitopes more accessible by favoring the RBD ‘up’ conformation. 17 We conclude that the in vitro binding and neutralizing properties of CoV-X2 make it preferable over its parental antibodies.…”

mentioning

confidence: 86%

Bispecific antibody neutralizes circulating SARS-CoV-2 variants, prevents escape and protects mice from disease

Gasparo¹,

Pedotti²,

Simonelli³

et al. 2021

Preprint

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SummaryNeutralizing antibodies targeting the receptor binding domain (RBD) of the SARS-CoV-2 Spike (S) are among the most promising approaches against coronavirus disease 2019 (COVID-19)1,2. We developed a bispecific, IgG1-like molecule based on two antibodies derived from COVID-19 convalescent donors, C121 and C1353. CoV-X2 simultaneously binds two independent sites on the RBD and, unlike its parental antibodies, completely prevents S binding to Angiotensin-Converting Enzyme 2 (ACE2), the virus cellular receptor. Furthermore, CoV-X2 recognizes a broad panel of RBD variants and neutralizes SARS-CoV-2 and the escape mutants generated by the single monoclonals at sub-nanomolar concentrations. In a novel model of SARS-CoV-2 infection with lung inflammation, CoV-X2 protects mice from disease and suppresses viral escape. Thus, simultaneous targeting of non-overlapping RBD epitopes by IgG-like bispecific antibodies is feasible and effective, combining into a single molecule the advantages of antibody cocktails.

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“…Several studies pointed to the hypothesis that this mutation confers enhanced transmissibility [ 23 ], and may increase infectivity by assembling more functional S protein into the virion [ 24 , 25 ]. The cryo-electron microscopy structure of the G614 S variant showed that it adopts a predominantly open conformation, likely promoting a more proficient binding to ACE2, whereas the D614 S is mostly closed [ 26 ]. This may account for virus’ observed augmented infectivity and its current predominance.…”

Section: Introductionmentioning

confidence: 99%

Altered Local Interactions and Long-Range Communications in UK Variant (B.1.1.7) Spike Glycoprotein

Borocci

Cerchia

Grottesi

et al. 2021

IJMS

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The COVID-19 pandemic is caused by SARS-CoV-2. Currently, most of the research efforts towards the development of vaccines and antibodies against SARS-CoV-2 were mainly focused on the spike (S) protein, which mediates virus entry into the host cell by binding to ACE2. As the virus SARS-CoV-2 continues to spread globally, variants have emerged, characterized by multiple mutations of the S glycoprotein. Herein, we employed microsecond-long molecular dynamics simulations to study the impact of the mutations of the S glycoprotein in SARS-CoV-2 Variant of Concern 202012/01 (B.1.1.7), termed the “UK variant”, in comparison with the wild type, with the aim to decipher the structural basis of the reported increased infectivity and virulence. The simulations provided insights on the different dynamics of UK and wild-type S glycoprotein, regarding in particular the Receptor Binding Domain (RBD). In addition, we investigated the role of glycans in modulating the conformational transitions of the RBD. The overall results showed that the UK mutant experiences higher flexibility in the RBD with respect to wild type; this behavior might be correlated with the increased transmission reported for this variant. Our work also adds useful structural information on antigenic “hotspots” and epitopes targeted by neutralizing antibodies.

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The effect of the D614G substitution on the structure of the spike glycoprotein of SARS-CoV-2

Cited by 144 publications

References 31 publications

The Impact on Infectivity and Neutralization Efficiency of SARS-CoV-2 Lineage B.1.351 Pseudovirus

The Impact on Infectivity and Neutralization Efficiency of SARS-CoV-2 Lineage B.1.351 Pseudovirus

Bispecific antibody neutralizes circulating SARS-CoV-2 variants, prevents escape and protects mice from disease

Altered Local Interactions and Long-Range Communications in UK Variant (B.1.1.7) Spike Glycoprotein

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