Structural basis for the different states of the spike protein of SARS-CoV-2 in complex with ACE2

Yan, Renhong; Zhang, Yuanyuan; Li, Yaning; Ye, Fangfei; Guo, Yingying; Xia, Lu; Zhong, Xinyue; Chi, Ximin; Zhou, Qiang

doi:10.1038/s41422-021-00490-0

Cited by 83 publications

(100 citation statements)

References 14 publications

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“…[ 24 , 26 ]. Several structural and dynamic studies at the molecular level show that SARS-CoV-2 RBDs have to adapt open conformation (also known as “up” or “standing”) to effectively bind to ACE2 receptors [ 8 , 16 , 61 , 62 ]. So far, mutations in non-RBD residues, such as the D614G variant, can populate RBD open conformation rather than closed conformations [ 63 ].…”

Section: Discussionmentioning

confidence: 99%

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Mutations of SARS-CoV-2 RBD May Alter Its Molecular Structure to Improve Its Infection Efficiency

Alaofi

Shahid

2021

Biomolecules

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The receptor-binding domain (RBD) of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) mediates the viral–host interaction and is a target for most neutralizing antibodies. Nevertheless, SARS-CoV-2 RBD mutations pose a threat due to their role in host cell entry via the human angiotensin-converting enzyme 2 receptor that might strengthen SARS-CoV-2 infectivity, viral load, or resistance against neutralizing antibodies. To understand the molecular structural link between RBD mutations and infectivity, the top five mutant RBDs (i.e., N501Y, E484K L452R, S477N, and N439K) were selected based on their recorded case numbers. These mutants along with wild-type (WT) RBD were studied through all-atom molecular dynamics (MD) simulations of 100 ns. The principal component analysis and the free energy landscape were used too. Interestingly, N501Y, N439K, and E484K mutations were observed to increase the rigidity in some RBD regions while increasing the flexibility of the receptor-binding motif (RBM) region, suggesting a compensation of the entropy penalty. However, S477N and L452R RBDs were observed to increase the flexibility of the RBM region while maintaining similar flexibility in other RBD regions in comparison to WT RBD. Therefore, both mutations (especially S477N) might destabilize the RBD structure, as loose conformation compactness was observed. The destabilizing effect of S477N RBD was consistent with previous work on S477N mutation. Finally, the free energy landscape results showed that mutations changed WT RBD conformation while local minima were maintained for all mutant RBDs. In conclusion, RBD mutations definitely impact the WT RBD structure and conformation as well as increase the binding affinity to angiotensin-converting enzyme receptor.

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Section: Discussionmentioning

confidence: 99%

“…Structural components of SARS-CoV-2 have been extensively studied [ 7 , 8 , 9 , 10 , 11 ]. On mature virus, the spike (S) glycoprotein on the surface of SARS-CoV-2 is composed of an extracellular domain (EC), transmembrane (anchor) domain, and short intracellular tail domain (IC) [ 11 , 12 ].…”

Section: Introductionmentioning

confidence: 99%

Mutations of SARS-CoV-2 RBD May Alter Its Molecular Structure to Improve Its Infection Efficiency

Alaofi

Shahid

2021

Biomolecules

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“…Spike protein was modeled using Pymol version 2.4.1 and the protein data bank trimeric spike protein structure 7DX0 in which one of the spike monomers’ receptor binding domains adopts the “up” conformation 3 . In some cases, specific spike variant residues were not modeled in the original structure and adjacent residues were highlighted as representative.…”

Section: Methodsmentioning

confidence: 99%

SARS -CoV-2 T-cell immunity to variants of concern following vaccination

Gallagher

Leick

Larson

et al. 2021

Preprint

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Recently, two mRNA vaccines to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have become available, but there is also an emergence of SARS-CoV-2 variants with increased transmissibility and virulence. A major concern is whether the available vaccines will be equally effective against these variants. The vaccines are designed to induce an immune response against the SARS-CoV-2 spike protein, which is required for viral entry to host cells. Immunity to SARS-CoV-2 is often evaluated by antibody production, while less is known about the T-cell response. Here we developed, characterized, and implemented two standardized, functional assays to measure T-cell immunity to SARS-CoV-2 in uninfected, convalescent, and vaccinated individuals. We found that vaccinated individuals had robust T-cell responses to the wild type spike and nucleocapsid proteins, even more so than convalescent patients. We also found detectable but diminished T-cell responses to spike variants (B.1.1.7, B.1.351, and B.1.1.248) among vaccinated but otherwise healthy donors. Since decreases in antibody neutralization have also been observed with some variants, investigation into the T-cell response to these variants as an alternative means of viral control is imperative. Standardized measurements of T-cell responses to SARS-CoV-2 are feasible and can be easily adjusted to determine changes in response to variants.

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“…The RBD-hACE2 focused structures highlight the main interactions leading to receptor recognition by SARS-CoV-2, and they are critical for spike protein function. Nevertheless, the spike protein has additional functions in budding and cell fusion, mainly through conformational changes caused by the interactions with hACE2 [ 1 , 28 , 56 ]. Structure determination for the full spike protein will necessarily have limitations due to its size, and usually other structures are used to build the RBD portion of the structure [ 39 ].…”

Section: Discussionmentioning

confidence: 99%

“…Structure determination for the full spike protein will necessarily have limitations due to its size, and usually other structures are used to build the RBD portion of the structure [ 39 ]. However, they give an important insight into the major conformational changes to the entire protein and into critical steps culminating in cell fusion and infection [ 39 , 56 ].…”

Section: Discussionmentioning

confidence: 99%

SARS-CoV-2 Virus−Host Interaction: Currently Available Structures and Implications of Variant Emergence on Infectivity and Immune Response

Queirós-Reis

Silva

Gonçalves

et al. 2021

IJMS

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Coronavirus disease 19, or COVID-19, is an infection associated with an unprecedented worldwide pandemic caused by the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), which has led to more than 215 million infected people and more than 4.5 million deaths worldwide. SARS-CoV-2 cell infection is initiated by a densely glycosylated spike (S) protein, a fusion protein, binding human angiotensin converting enzyme 2 (hACE2), that acts as the functional receptor through the receptor binding domain (RBD). In this article, the interaction of hACE2 with the RBD and how fusion is initiated after recognition are explored, as well as how mutations influence infectivity and immune response. Thus, we focused on all structures available in the Protein Data Bank for the interaction between SARS-CoV-2 S protein and hACE2. Specifically, the Delta variant carries particular mutations associated with increased viral fitness through decreased antibody binding, increased RBD affinity and altered protein dynamics. Combining both existing mutations and mutagenesis studies, new potential SARS-CoV-2 variants, harboring advantageous S protein mutations, may be predicted. These include mutations S13I and W152C, decreasing antibody binding, N460K, increasing RDB affinity, or Q498R, positively affecting both properties.

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Structural basis for the different states of the spike protein of SARS-CoV-2 in complex with ACE2

Cited by 83 publications

References 14 publications

Mutations of SARS-CoV-2 RBD May Alter Its Molecular Structure to Improve Its Infection Efficiency

Mutations of SARS-CoV-2 RBD May Alter Its Molecular Structure to Improve Its Infection Efficiency

SARS -CoV-2 T-cell immunity to variants of concern following vaccination

SARS-CoV-2 Virus−Host Interaction: Currently Available Structures and Implications of Variant Emergence on Infectivity and Immune Response

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