Overall, the SARS-CoV-2 S structure shows many similarities to those of other coronavirus spike proteins. Soon after, structures of detergent-solubilized, full-length S proteins in both prefusion and postfusion conformations, as well as those of the intact S trimer on the virion surface, studied by cryo-electron tomography, were also reported ( Figure 1b and c). Structures of S protein fragments derived from the Wuhan-Hu-1 strain, including the S ectodomain stabilized in its prefusion conformation, RBD-ACE2 complexes, and segments of S2 in the postfusion state, were determined within the first several months of the pandemic. ), and SARS-CoV S2 in the postfusion state (PDB ID: 6M3W Ref. (e) MHV (mouse hepatitis virus) S2 in the postfusion state (PDB ID: 6B3O Ref. ), the stabilized soluble SARS-CoV-2 S trimer in the one RBD-up conformation (PDB ID: 6VSB Ref. (d) Additional structures of coronavirus S proteins, including the full-length SARS-CoV-2 S trimer carrying G614 in the one RBD-up conformation (PDB ID: 7KRR), the stabilized soluble SARS-CoV-2 S trimer in the RBD-down conformation (PDB ID: 6VXX Ref. Right: cryo-EM structure of the full-length S2 trimer in the postfusion conformation (PDB ID: 6XRA). ), fitted with the structure of the purified protein (PDB ID: 6XRA Ref. (c) Left: viral SARS-CoV-2 S2 trimer in the postfusion conformation (EMD-30428 Ref. Right: cryo-EM structure of the full-length S trimer in the RBD-down conformation (PDB ID: 6XR8). ), fitted with the structures of purified proteins (PDB ID: 7KRR and 6XR8 Refs. (b) Left: viral SARS-CoV-2 S trimer in the prefusion conformation (EMD-30430 Ref. Segments of S1 and S2 include: NTD, N-terminal domain RBD, receptor-binding domain CTD1, C-terminal domain 1 CTD2, C-terminal domain 2 S1/S2, S1/S2 cleavage site S2′, S2′ cleavage site FP, fusion peptide FPPR, fusion peptide proximal region HR1, heptad repeat 1 CH, central helix region CD, connector domain HR2, heptad repeat 2 TM, transmembrane anchor CT, cytoplasmic tail and tree-like symbols for glycans. (a) Schematic representation of the SARS-CoV-2 spike protein organization. S1 can be further divided into N-terminal domain (NTD), receptor-binding domain (RBD) and C-terminal domains (CTD1 and CTD2), while S2 includes fusion peptide (FP), fusion-peptide proximal region (FPPR), heptad repeat 1 (HR1), central helix (CH), connector domain (CD), heptad repeat 2 (HR2), transmembrane segment (TM) and the cytoplasmic tail (CT), depicted in Figure 1a.ĭistinct conformational states of the SARS-CoV-2 spike protein. The full-length S protein of the Wuhan-Hu-1 strain from the initial outbreak has 1273 amino acid residues, including a N-terminus signal peptide, a receptor-binding fragment S1 and a fusion fragment S2. The protein is heavily glycosylated with each protomer containing 22 N-linked glycosylation sites. It binds to the receptor angiotensin-converting enzyme 2 (ACE2) on a host cell and undergo large structural rearrangements to promote membrane fusion. The SARS-CoV-2 spike glycoprotein is a type I membrane protein ( Figure 1Ī), which forms a trimer, anchored to the viral membrane by its transmembrane segment, while decorating the virion surface with it large ectodomain ( Figure 1b). Overall structure of SARS-CoV-2 S protein Here we summarize our current knowledge on the structure of the SARS-CoV-2 S protein and discuss the implications for vaccines and therapeutics. Remarkable progress in the structural biology of SARS-CoV-2 S protein has been made since the initial outbreak of the virus, substantially advancing our molecular understanding of the viral entry process. The protein is therefore an important target for development of diagnostics, therapeutics and vaccines. This first critical step of viral infection is catalyzed by its trimeric spike (S) protein, which decorates the virion surface as a major antigen and induces neutralizing antibody responses. Coronaviruses (CoVs) are enveloped positive-stranded RNA viruses that enter a host cell by fusion of its envelope lipid bilayer with the target cell membrane. A deep understanding of the structure-function relationships of viral proteins and relevant host factors will be required in order to meet these needs. There are urgent needs for innovative vaccine and therapeutic strategies to control this unprecedented crisis, as well as potential future needs if it becomes seasonal with continuous emergence of new variants. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causative agent of the COVID-19 (coronavirus disease 2019) pandemic, and its infection has led to millions of lives lost and devastating socio-economic consequences throughout the globe.
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