Multiple capsid-stabilizing interactions revealed in a high-resolution structure of an emerging picornavirus causing neonatal sepsis

Shabih Shakeel, Brenda M. Westerhuis, Ausra Domanska, Roman I. Koning, Rishi Matadeen, Abraham J. Koster, Arjen Q. Bakker, Tim Beaumont, Katja C. Wolthers () and Sarah J. Butcher ()
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Shabih Shakeel: Institute of Biotechnology and Department of Biological Sciences
Brenda M. Westerhuis: Laboratory of Clinical Virology, Academic Medical Center, Meibergdreef 9
Ausra Domanska: Institute of Biotechnology and Department of Biological Sciences
Roman I. Koning: Leiden University Medical Center, Postal Zone S1-P, P.O. Box 9600
Rishi Matadeen: Netherlands Centre for Electron Nanoscopy, Institute of Biology, Ensteinweg 55
Abraham J. Koster: Leiden University Medical Center, Postal Zone S1-P, P.O. Box 9600
Arjen Q. Bakker: AIMM Therapeutics, Academic Medical Center, Meibergdreef
Tim Beaumont: AIMM Therapeutics, Academic Medical Center, Meibergdreef
Katja C. Wolthers: Laboratory of Clinical Virology, Academic Medical Center, Meibergdreef 9
Sarah J. Butcher: Institute of Biotechnology and Department of Biological Sciences

Nature Communications, 2016, vol. 7, issue 1, 1-8

Abstract: 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.

Date: 2016
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DOI: 10.1038/ncomms11387

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