Prefusion structure of a human coronavirus spike protein

By R. Kirchdoerfer, C. Cottrell, Nianshuang Wang, J. Pallesen, Hadi M. Yassine, H. Turner, Kizzmekia S. Corbett, Barney S. Graham, J. McLellan, A. Ward. Nature, 2016

716 citations recorded by the source corpus.

HKU1 is a human betacoronavirus that causes mild yet prevalent respiratory disease, and is related to the zoonotic SARS and MERS betacoronaviruses, which have high fatality rates and pandemic potential. Cell tropism and host range is determined in part by the coronavirus spike (S) protein, which binds cellular receptors and mediates membrane fusion. As the largest known class I fusion protein, its size and extensive glycosylation have hindered structural studies of the full ectodomain, thus preventing a molecular understanding of its function and limiting development of effective interventions. Here we present the 4.0 Å resolution structure of the trimeric HKU1 S protein determined using single-particle cryo-electron microscopy. In the pre-fusion conformation, the receptor-binding subunits, S1, rest above the fusion-mediating subunits, S2, preventing their conformational rearrangement. Surprisingly, the S1 C-terminal domains are interdigitated and form extensive quaternary interactions that occlude surfaces known in other coronaviruses to bind protein receptors. These features, along with the location of the two protease sites known to be important for coronavirus entry, provide a structural basis to support a model of membrane fusion mediated by progressive S protein destabilization through receptor binding and proteolytic cleavage. These studies should also serve as a foundation for the structure-based design of betacoronavirus vaccine immunogens.

Subfields: Animal Science and Zoology, Infectious Diseases

View Paper: https://www.semanticscholar.org/paper/c058c12c67d18b0f3ab01e26a30b2769854c346d

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Citations in the corpus

Glycan shield and epitope masking of a coronavirus spike protein observed by cryo-electron microscopy (2016, background): “Visualization of the glycan shield obstructing access to the S surface and deciphering the molecular trickery used by some coronaviruses provide a rational basis for understanding the accessibility to neutralizing antibodies and may pave the way for guiding future design of immunogens or therapeutic”
Cryo-EM structures of MERS-CoV and SARS-CoV spike glycoproteins reveal the dynamic receptor binding domains (2017, neutral): “Recently, three pioneering studies on cryo-EM structures of the S ectodomain from MHV and hCoVs HKU1 and NL63 have revealed a similar overall structural fold of the full-length S protein 27–29 .”
Structural insights into coronavirus entry (2019, background): “Domain A and domain 0 adopt a galectin-like β-sandwich fold conserved across all CoV genera (Kirchdoerfer et al., 2016; Peng et al., 2011, 2012; Walls et al., 2016a) (Fig.”
Uncanny similarity of unique inserts in the 2019-nCoV spike protein to HIV-1 gp120 and Gag (2020, background): “The comparison of the modelled structure reveals that although inserts 1,2 and 3 are at non-contiguous locations in the protein primary sequence, they fold to constitute the part of glycoprotein binding site that recognizes the host receptor (Kirchdoerfer et al., 2016) (Figure 4).”
Structure, Function, and Evolution of Coronavirus Spike Proteins (2016, methodology): “The prefusion structures of betacoronavirus MHV and HKU1 spikes were recently determined using cryo–electron microscopy (15, 16) (Figure 2a).”
SARS-CoV-2 mRNA Vaccine Design Enabled by Prototype Pathogen Preparedness (2020, positive): “Subsequently, we identified 2 proline substitutions (2P) at the apex of the central helix and heptad repeat 1 that effectively stabilized MERS-CoV, SARS-CoV and human coronavirus HKU1 S proteins in the prefusion conformation 1,11,12 .”
Glycan Shield and Fusion Activation of a Deltacoronavirus Spike Glycoprotein Fine-Tuned for Enteric Infections (2017, background): “studies showed that domain A mediates these interactions and mapped key residues 268 involved(25, 45) and nanoparticle-displayed multimeric OC43 S1 subunit exhibited high 269”
Structures of Human Antibodies Bound to SARS-CoV-2 Spike Reveal Common Epitopes and Recurrent Features of Antibodies (2020, neutral): “Nevertheless, the 3D structures of S protein trimer ectodomains are similar to each other and to other coronavirus S structures, including the finding of flexible RBDs (S1 domains) that can be in various ‘‘up’’ conformations or in the ‘‘down’’ conformation of the closed pre-fusion trimer (Kirchdoerf”
Molecular Evolution of Human Coronavirus Genomes (2016, neutral): “HCoV-HKU1 The structure of the S protein of HKU1 was recently solved; the glycan-binding site is located in the NTD and is conserved with bovine coronavirus (BCoV) S1 [63].”
Cryo-EM Structure of the 2019-nCoV Spike in the Prefusion Conformation (2020, background): “Like all 65 previously reported coronavirus S ectodomain structures, the density for 2019-nCoV S begins to 66 fade after the connector domain (CD), reflecting the flexibility of the heptad repeat 2 (HR2) 67 domain in the prefusion conformation (Supplementary Figure 4A) (13, 16-18).”