Cell: Reveals Structure, Function and Antigenicity of Novel Coronavirus SARS-CoV-2 Spike Glycoprotein

Since the beginning of the 21st century, three coronaviruses have crossed species barriers, causing fatal pneumonia in humans: Severe Acute Respiratory Syndrome (SARS) Coronavirus (SARS-CoV), Middle East Respiratory Syndrome (MERS) Coronavirus (MERS-CoV) and SARS-CoV-2 (formerly known as Novel Coronavirus 2019, 2019-nCoV).

MERS-CoV is thought to originate in bats, but the intermediate host that facilitated its spillover into humans was the unimodal camel. SARS-CoV and SARS-CoV-2 are closely related to each other and both originate from bats, so bats are most likely the natural hosts for these two viruses. Although civet has been recognized as an intermediate host for transmitting the zoonotic pathogen SARS-CoV between bats and humans, the intermediate host for SARS-CoV-2 remains unknown. To date, no drug or vaccine has been approved against any human coronavirus.

Figure 1 Cryo-EM structure of SARS-CoV-2 S glycoprotein

Because the coronavirus S protein is exposed on the virus surface and mediates virus entry into host cells, it is the main target for neutralizing antibodies after infection, and it is also the focus of drug development and vaccine design. S protein trimers are extensively modified by N-linked glycans, which is essential for their proper folding and regulating the accessibility of host proteases and neutralizing antibodies. Dr. David Veesler and his team from the Department of Biochemistry at the University of Washington School of Medicine and his team previously described the isolation of strong human neutralizing antibodies from the rare memory B cells of SARS CoV or mers cov infected patients, which combined with the S protein of SARS CoV or mers CoV, providing molecular level information for the mechanism of competitive inhibition domain B attaching to the host receptor as the human neutralizing antibody against the S protein of SARS CoV. The anti-SARS-CoV antibody S230 can also functionally mimic receptor attachment and promote a conformational rearrangement of viral spike fusions through a molecular ratcheting mechanism that reveals the unique properties of this coronavirus membrane fusion activation.

In a new study, Veesler’s team reported that human ACE2 regulates SARS-CoV-2 S protein-mediated cell entry, identifying it as a functional receptor for this emerging coronavirus. The affinity of domain B of the SARS-CoV-2 S protein to human ACE2 is comparable to the domain B of the S protein from SARS-CoV isolates associated with the 2002-2003 SARS epidemic. This indicates that domain B of the SARS-CoV-2 S protein has a high binding affinity to human ACE2. Tight integration with human ACE2 can partially explain the effective transmission of SARS-CoV-2 in humans, as is the case with SARS-CoV. The relevant research results were published online in the journal Cell in the form of a manuscript.

They identified unexpected furin cleavage sites at the S1 / S2 subunit boundary of the SARS-CoV-2 S protein. This site is cleaved during S protein biosynthesis, a new feature that distinguishes this coronavirus from SARS-CoV and SARSr-CoV. They analyzed the cryo-EM structure of the trimer of the extracellular domain of the SARS-CoV-2 S protein and revealed that it has multiple domain B conformations. They confirmed that SARS-CoV S protein mouse polyclonal serum effectively inhibited SARS-CoV-2 S pseudovirus from entering target cells. These results pave the way for the design of vaccines that can prevent SARS-CoV-2, SARS-CoV and SARS-CoV widely.

Interestingly, the SARS-CoV-2 S protein has a furin cleavage site at the S1 / S2 border, which is processed during biosynthesis. The presence of furin cleavage sites distinguishes the SARS-CoV-2 S protein from the SARS-CoV S protein and the SARSr-CoV S protein. This is because the latter two have a monobasic cleavage site at the S1 / S2 boundary, and this cleavage site is processed when it enters the target cell. Veesler’s team speculated that compared to SARS-CoV, the almost ubiquitous expression of furin-like protease may be involved in expanding the host cell and tissue tropism of SARS-CoV-2, and increasing its spread and / or altering its pathogenicity.

These findings also suggest that in serological studies using S protein trimers, it may be difficult to distinguish exposure to new coronavirus from exposure to other SARSr-CoV. Specific test methods need to be designed, but the results of this article provide a structural framework that will support ongoing vaccine design work.


1. Alexandra C. Walls et al. Structure, function and antigenicity of the SARS-CoV-2 spike glycoprotein. Cell, 2020, doi:10.1016/j.cell.2020.02.058.