Abstract
The poorly studied picornavirus, human parechovirus 3 (HPeV3) causes neonatal sepsis with no therapies available. Our 4.3-Å resolution structure of HPeV3 on its own and at 15 Å resolution in complex with human monoclonal antibody Fabs demonstrates the expected picornavirus capsid structure with three distinct features. First, 25% of the HPeV3 RNA genome in 60 sites is highly ordered as confirmed by asymmetric reconstruction, and interacts with conserved regions of the capsid proteins VP1 and VP3. Second, the VP0 N terminus stabilizes the capsid inner surface, in contrast to other picornaviruses where on expulsion as VP4, it forms an RNA translocation channel. Last, VP1's hydrophobic pocket, the binding site for the antipicornaviral drug, pleconaril, is blocked and thus inappropriate for antiviral development. Together, these results suggest a direction for development of neutralizing antibodies, antiviral drugs based on targeting the RNA–protein interactions and dissection of virus assembly on the basis of RNA nucleation.
Highlights
The poorly studied picornavirus, human parechovirus 3 (HPeV3) causes neonatal sepsis with no therapies available
The virion structure shows that VP1 pocket-binding drugs, such as pleconaril, are unlikely to bind to HPeV; that VP0 is an important protein for stabilizing the inner surface of the capsid, and that the assembly of HPeV is most likely controlled by multiple interactions of the genome with the capsid, through conserved amino acids in VP1 and VP3 and stem-loop structures in the RNA
Similar to many picornaviruses[4], HPeV3 possesses an open channel at each fivefold vertex[5] (Supplementary Fig. 3) and a canyon for potential receptor and antibody binding, it is wide and shallow (Fig. 1a)
Summary
The poorly studied picornavirus, human parechovirus 3 (HPeV3) causes neonatal sepsis with no therapies available. We utilized cryo-electron microscopy and image reconstruction to analyse the structure of HPeV3 on its own and in complex with a human monoclonal antibody Fab. The virion structure shows that VP1 pocket-binding drugs, such as pleconaril, are unlikely to bind to HPeV; that VP0 is an important protein for stabilizing the inner surface of the capsid, and that the assembly of HPeV is most likely controlled by multiple interactions of the genome with the capsid, through conserved amino acids in VP1 and VP3 and stem-loop structures in the RNA. We isolated and characterized an HPeV3-specific human monoclonal antibody, which could be very useful for advancing virus diagnostics and studying virus–host interactions.
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