Abstract
The coronavirus S-protein mediates receptor binding and fusion of the viral and host cell membranes. In HCoV-229E, its receptor binding domain (RBD) shows extensive sequence variation but how S-protein function is maintained is not understood. Reported are the X-ray crystal structures of Class III-V RBDs in complex with human aminopeptidase N (hAPN), as well as the electron cryomicroscopy structure of the 229E S-protein. The structures show that common core interactions define the specificity for hAPN and that the peripheral RBD sequence variation is accommodated by loop plasticity. The results provide insight into immune evasion and the cross-species transmission of 229E and related coronaviruses. We also find that the 229E S-protein can expose a portion of its helical core to solvent. This is undoubtedly facilitated by hydrophilic subunit interfaces that we show are conserved among coronaviruses. These interfaces likely play a role in the S-protein conformational changes associated with membrane fusion.
Highlights
Coronaviruses are enveloped RNA viruses found in mammals and birds (Graham et al, 2013; Su et al, 2016)
To gain insight into how loop variation is accommodated while maintaining receptor binding, we have determined the structures of the Class III-V receptor binding domain (RBD) in complex with human aminopeptidase N (hAPN)
The 287–291 segment of hAPN is a surface-exposed b-strand and these hydrogen bonds satisfy all its exposed backbone amide and carbonyl groups. These common hydrogen bonds involve the side chains of Loop 1 residue Asn 319 and hAPN residue Asp 288. The importance of these core interactions is underscored by the fact that Gly 315, Cys 317, Asn 319, and Cys 320 correspond to four of the six residues that are absolutely conserved among the receptor binding loops of all 229E isolates sequenced (Wong et al, 2017) (Figure 1d, Figure 1—figure supplement 1)
Summary
Coronaviruses are enveloped RNA viruses found in mammals and birds (Graham et al, 2013; Su et al, 2016). HCoV-229E uses human aminopeptidase N (hAPN) as receptor (Yeager et al, 1992) and it was recently shown in a cell-based entry assay that the camel 229E-like CoV can use hAPN (Corman et al, 2016). These viruses might bind their host APNs in a structurally conserved fashion, it should be noted that the porcine alphacoronavirus, PRCoV, binds to a site on porcine APN that differs from the site at which HCoV-229E binds to hAPN
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