Effect of SARS-CoV-2 B.1.1.7 mutations on spike protein structure and function

Yang, Tzu-Jing; Yu, Pei-Yu; Chang, Yuan-Chih; Liang, Kang-Hao; Tso, Hsian-Cheng; Ho, Meng‐Ru; Chen, Wan‐Yu; Lin, Hsiu-Ting; Wu, Han‐Chung; Hsu, Shang-Te Danny

doi:10.1038/s41594-021-00652-z

Cited by 144 publications

(160 citation statements)

References 43 publications

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“…Nevertheless, all three nAbs potently neutralize the most problematic Delta variant, as well as the Kappa variant. According to our previously reported high-resolution cryo-EM structures of RBD-chAb-15, -25 and -45 in complex with S variants 32,41 , RBD-chAb-45 binds to the site Ia/class 2 on RBD, which is accessible regardless of the RBD up/down conformation 8,12 , while RBD-chAb-15 and -25 bind to different regions within the epitope Ib/class 1 on RBD, which is only accessible in the RBD-up state 8,12 . The versatility of RBD-chAb-45 in recognizing different states of the RBD is manifested in the lowest IC50 values against all four pseudovirus variants (Fig.…”

Section: Discussionmentioning

confidence: 89%

“…A. ), which contains a foldon trimerization domain based on phage T4 fibritin followed by a c-Myc epitope and a hexa-repeat histidine tag as previously described 32,42 . All constructs contained the fm2P modification, which is defined as the tandem proline replacement (2P, 986 KV 987 → 986 PP 987 ) and the furin cleavage site mutation (fm, 682 RRAR 685 → 682 GSAG 685 ), for stabilizing the S protein in a prefusion state 7 .…”

Section: Expression and Purification Of S-beta Gamma Delta And Kappa Variantsmentioning

confidence: 99%

“…The plasmids of all S variants were transiently expressed in HEK293 Freestyle cells with polyethylenimine. Recombinant protein purification was carried out as previously described 32 . Briefly, the culture medium was incubated with HisPur Cobalt Resin (Thermo Fisher Scientific, U. S.…”

Section: Expression and Purification Of S-beta Gamma Delta And Kappa Variantsmentioning

confidence: 99%

“…The production of recombinant sfGFP-ACE2 (hereafter ACE2) was described previously 32 . Briefly, transient expression of recombinant ACE2 was achieved in Expi293 cells.…”

Section: Expression and Purification Of Sfgfp-ace2mentioning

confidence: 99%

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Structure-activity relationships of B.1.617 and other SARS-CoV-2 spike variants

Yang

Chang

et al. 2021

Preprint

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The surge of COVID-19 infection cases is spurred by emerging SARS-CoV-2 variants such as B.1.617. Here we report 38 cryo-EM structures, corresponding to the spike protein of the Beta (B.1.351), Gamma (P.1), Delta (B.1.617.2) and Kappa (B.1.617.1) variants in different functional states with and without its receptor, ACE2. Mutations on the N-terminal domain not only alter the conformation of the highly antigenic supersite of the Delta variant, but also remodel the glycan shield by deleting or adding N-glycans of the Delta and Gamma variants, respectively. Substantially enhanced ACE2 binding was observed for all variants, whose mutations on the receptor binding domain modulate the electrostatics of the binding interfaces. Despite their abilities to escape host immunity, all variants can be potently neutralized by three unique antibodies.

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Section: Discussionmentioning

confidence: 89%

Section: Expression and Purification Of S-beta Gamma Delta And Kappa Variantsmentioning

confidence: 99%

Section: Expression and Purification Of S-beta Gamma Delta And Kappa Variantsmentioning

confidence: 99%

“…The production of recombinant sfGFP-ACE2 (hereafter ACE2) was described previously 32 . Briefly, transient expression of recombinant ACE2 was achieved in Expi293 cells.…”

Section: Expression and Purification Of Sfgfp-ace2mentioning

confidence: 99%

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Structure-activity relationships of B.1.617 and other SARS-CoV-2 spike variants

Yang

Chang

et al. 2021

Preprint

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“…Spike trimer structures have been solved in receptor bound or unbound forms (31, 32) and it has been demonstrated that the conformation of the Spike (open or closed) is of critical relevance for receptor interactions (33, 34) . Importantly, mutations outside the RBD that alter the Spike conformation have been reported to also affect viral infectivity and receptor binding (35, 36) . To test whether our observations on the increased affinity of VOC RBD/APN01 interaction is also observed in the context of the full-length Spike, we assessed APN01 binding to recombinant prefusion trimeric SARS-CoV-2 Spike proteins.…”

Section: Resultsmentioning

confidence: 99%

Clinical grade ACE2 as a universal agent to block SARS-CoV-2 variants

Wirnsberger

Monteil

Eaton³

et al. 2021

Preprint

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The recent emergence of multiple SARS-CoV-2 variants has caused considerable concern due to reduced vaccine efficacy and escape from neutralizing antibody therapeutics. It is therefore paramount to develop therapeutic strategies that inhibit all known and future SARS-CoV-2 variants. Here we report that all SARS-CoV-2 variants analyzed, including variants of concern (VOC) Alpha, Beta, Gamma, and Delta, exhibit enhanced binding affinity to clinical grade and phase 2 tested recombinant human soluble ACE2 (APN01). Importantly, soluble ACE2 neutralized infection of VeroE6 cells and human lung epithelial cells by multiple VOC strains with markedly enhanced potency when compared to reference SARS-CoV-2 isolates. Effective inhibition of infections with SARS-CoV-2 variants was validated and confirmed in two independent laboratories. These data show that SARS-CoV-2 variants that have emerged around the world, including current VOC and several variants of interest, can be inhibited by soluble ACE2, providing proof of principle of a pan-SARS-CoV-2 therapeutic.

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Computation of the Binding Energies between Human ACE2 and Spike RBDs of the Original Strain, Delta and Omicron Variants of the SARS‐CoV‐2: A DFT Simulation Approach

Yamaçli

Avcı

2022

Advcd Theory and Sims

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The receptor binding domain (RBD) of SARS‐CoV‐2 binds to human ACE2 leading to infection. In this study, the complexes that are formed by the attachment of the SARS‐CoV‐2 spike RBDs of the original strain, delta and omicron variants to the human ACE2 are investigated via density functional theory (DFT) simulations to obtain binding energies. The DFT computations are performed without fragmenting the interfaces to involve longer‐range interactions for improved accuracy, which is one of the primary features of the approach used in this study. Basis set superposition error corrections and van der Waals dispersions are also included in the DFT simulations. The binding energies of the SARS‐CoV‐2 spike RBDs of the original strain, delta and omicron variants to the human ACE2 are computed as −4.76, −6.68, and −11.77 eV, respectively. These binding energy values indicate that the binding of the omicron variant to the ACE2 is much more favorable than the binding of the original strain and the delta variant, which constitute a molecular reason for the takeover of the omicron variant. The binding energies and the decomposition of these energies found in this study are expected to aid in the development of neutralizing agents.

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Effect of SARS-CoV-2 B.1.1.7 mutations on spike protein structure and function

Cited by 144 publications

References 43 publications

Structure-activity relationships of B.1.617 and other SARS-CoV-2 spike variants

Structure-activity relationships of B.1.617 and other SARS-CoV-2 spike variants

Clinical grade ACE2 as a universal agent to block SARS-CoV-2 variants

Computation of the Binding Energies between Human ACE2 and Spike RBDs of the Original Strain, Delta and Omicron Variants of the SARS‐CoV‐2: A DFT Simulation Approach

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