Abstract
Global emergencies caused by the severe acute respiratory syndrome coronavirus (SARS-CoV), Middle-East respiratory syndrome coronavirus (MERS-CoV) and SARS-CoV-2 significantly endanger human health. The spike (S) glycoprotein is the key antigen and its conserved S2 subunit contributes to viral entry by mediating host-viral membrane fusion. However, structural information of the post-fusion S2 from these highly pathogenic human-infecting coronaviruses is still lacking. We used single-particle cryo-electron microscopy to show that the post-fusion SARS-CoV S2 forms a further rotated HR1-HR2 six-helix bundle and a tightly bound linker region upstream of the HR2 motif. The structures of pre- and post-fusion SARS-CoV S glycoprotein dramatically differ, resembling that of the Mouse hepatitis virus (MHV) and other class I viral fusion proteins. This structure suggests potential targets for the development of vaccines and therapies against a wide range of SARS-like coronaviruses.
Highlights
Global emergencies caused by the severe acute respiratory syndrome coronavirus (SARSCoV), Middle-East respiratory syndrome coronavirus (MERS-CoV) and SARS-CoV-2 significantly endanger human health
We found that the linker regions upstream of the HR2 motifs that are critical for the formation of the HR1–HR2 six-helix bundle bind more tightly along the central stem region than the Mouse hepatitis virus (MHV) S glycoprotein, and that the HR1–HR2 six-helix bundle is more twisted leading to a less buried area between the HR1 and HR2 motifs
The upstream helix (UH), β-hairpin (BH) motif, and subdomain 3 (SD3) are located surrounding the C-terminus of the central HR1-central helix (CH) helices, which only partially cover the top of the central helical region
Summary
Global emergencies caused by the severe acute respiratory syndrome coronavirus (SARSCoV), Middle-East respiratory syndrome coronavirus (MERS-CoV) and SARS-CoV-2 significantly endanger human health. The structures of pre- and postfusion SARS-CoV S glycoprotein dramatically differ, resembling that of the Mouse hepatitis virus (MHV) and other class I viral fusion proteins. This structure suggests potential targets for the development of vaccines and therapies against a wide range of SARS-like coronaviruses. Detailed structural information about the SARS-CoV, MERS-CoV, and SARS-CoV-2 S2 fusion machineries is still required for further understanding of the mechanism of membrane fusion and the potential for developing broad-spectrum therapeutics against these human-infecting coronaviruses with serious pathogenicity. Comparison with the structure of the pre-fusion SARS-CoV S glycoprotein reveals dramatic conformational changes of the SARS-CoV S2 machinery during membrane fusion, resembling that of MHV and other class I fusion proteins. By mapping antibody and inhibitor targets within the conserved S2 subunit, we provide the structural basis for the development of vaccines and therapies that may suitable for treating a broad range of SARS-like coronaviruses
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