A highly conserved cryptic epitope in the receptor-binding domains of SARS-CoV-2 and SARS-CoV

By M. Yuan, Nicholas C. Wu, Xueyong Zhu, C. D. Lee, R. T. So, Huibin Lv, C. K. Mok, Ian A. Wilson. 2020

1,505 citations recorded by the source corpus.

Targeting the SARS-CoV-2 spike The surface of severe acute respiratory syndrome–coronavirus 2 (SARS-CoV-2) is decorated with trimeric spikes that bind to host cell receptors. These spikes also elicit an antibody response, so understanding antibody recognition may aid in vaccine design. Yuan et al. determined the structure of CR3022, a neutralizing antibody obtained from a convalescent SARS-CoV–infected patient, in complex with the receptor-binding domain of the SARS-CoV-2 spike. The antibody binds to an epitope conserved between SARS-CoV-2 and SARS-CoV that is distinct from the receptor-binding site. CR3022 likely binds more tightly to SARS-CoV because its epitope contains a glycan not present in SARS-CoV-2. Structural modeling showed that the epitope is only revealed when at least two of the three spike proteins are in a conformation competent to bind the receptor. Science, this issue p. 630 Structural studies show that a SARS antibody binds a conserved epitope on the viral spike distinct from the receptor-binding site. The outbreak of coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome–coronavirus 2 (SARS-CoV-2) has now become a pandemic, but there is currently very little understanding of the antigenicity of the virus. We therefore determined the crystal structure of CR3022, a neutralizing antibody previously isolated from a convalescent SARS patient, in complex with the receptor binding domain (RBD) of the SARS-CoV-2 spike (S) protein at 3.1-angstrom resolution. CR3022 targets a highly conserved epitope, distal from the receptor binding site, that enables cross-reactive binding between SARS-CoV-2 and SARS-CoV. Structural modeling further demonstrates that the binding epitope can only be accessed by CR3022 when at least two RBDs on the trimeric S protein are in the “up” conformation and slightly rotated. These results provide molecular insights into antibody recognition of SARS-CoV-2.

Subfields: Immunology, Infectious Diseases

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In Immunology

1. Kwinten Sliepen

In Infectious Diseases

1. D. Veesler
2. A. Walls
3. M. A. Tortorici
4. Andrew T. McGuire
5. Jesse D. Bloom
6. Kwinten Sliepen
7. Abdo A. Elfiky

Citations in the corpus

• Elicitation of Potent Neutralizing Antibody Responses by Designed Protein Nanoparticle Vaccines for SARS-CoV-2 (2020, neutral): “CR3022 is a weakly neutralizing Ab that binds to a conserved, cryptic epitope in the RBD (site II) that becomes accessible upon opening of two neighboring RBDs but is distinct from the RBM (site I), the surface of the RBD that interacts with ACE2 (Huo et al., 2020; Piccoli et al., 2020; ter Meulen e”
• Potent neutralizing antibodies from COVID-19 patients define multiple targets of vulnerability (2020, background): “COVA1-12 is highly overlapping with the epitope of COVA2-39, while COVA2-04 approaches the RBD at a unique angle that is somewhat similar to the cross-binding SARS-CoV-specific mAb CR3022 ( 39 ).”
• Complete mapping of mutations to the SARS-CoV-2 spike receptor-binding domain that escape antibody recognition (2020, positive): “All 10 antibodies bind the SARS-CoV-2 RBD with high affinity, but they differ in their neutralization potencies, extent to which they compete with ACE2 for RBD binding, and cross-reactivity with SARS-CoV-1 (Figure 2A) (Yuan et al., 2020; Zost et al., 2020a) .”
• Deep mutational scanning of SARS-CoV-2 receptor binding domain reveals constraints on folding and ACE2 binding (2020, positive): “Mutational constraint of antibody epitopes The RBD is the dominant target of neutralizing antibodies to SARS-CoV-2 (Brouwer et al., 2020; Cao et al., 2020; Ju et al., 2020; Premkumar et al., 2020; Rogers et al., 2020; Suthar et al., 2020; Yuan et al., 2020a; Zhang et al., 2020; Zost et al., 2020).”
• Tracking Changes in SARS-CoV-2 Spike: Evidence that D614G Increases Infectivity of the COVID-19 Virus (2020, positive): “Most target the trimeric Spike protein, which mediates host cell binding and entry and is the major target of neutralizing antibodies (Chen et al., 2020; Yuan et al., 2020).”