title: Multiple capsid-stabilizing interactions revealed in a high-resolution structure of an emerging picornavirus causing neonatal sepsis.
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.
authors.affiliation: Institute of Biotechnology and Department of Biological Sciences, Viikinkaari 1, 00014 University of Helsinki, Finland.
authors.forename: Shabih
authors.identifier: 0000-0003-3651-6087
authors.initials: S
authors.lastname: Shakeel
authors.affiliation: Department of Medical Microbiology, Laboratory of Clinical Virology, Academic Medical Center, Meibergdreef 9, 1105 Amsterdam, The Netherlands.
authors.forename: Brenda M
authors.initials: BM
authors.lastname: Westerhuis
authors.affiliation: Institute of Biotechnology and Department of Biological Sciences, Viikinkaari 1, 00014 University of Helsinki, Finland.
authors.forename: Ausra
authors.initials: A
authors.lastname: Domanska
authors.affiliation: Leiden University Medical Center, Department of Cell Biology, Postal Zone S1-P, P.O. Box 9600, 2300 RC Leiden, The Netherlands.
authors.forename: Roman I
authors.identifier: 0000-0001-6736-7147
authors.initials: RI
authors.lastname: Koning
authors.affiliation: Netherlands Centre for Electron Nanoscopy, Institute of Biology, Ensteinweg 55, 2333 RC Leiden, The Netherlands.
authors.forename: Rishi
authors.initials: R
authors.lastname: Matadeen
authors.affiliation: Leiden University Medical Center, Department of Cell Biology, Postal Zone S1-P, P.O. Box 9600, 2300 RC Leiden, The Netherlands.
authors.forename: Abraham J
authors.initials: AJ
authors.lastname: Koster
authors.affiliation: AIMM Therapeutics, Academic Medical Center, Meibergdreef 59, 1105 BA Amsterdam, The Netherlands.
authors.forename: Arjen Q
authors.initials: AQ
authors.lastname: Bakker
authors.affiliation: AIMM Therapeutics, Academic Medical Center, Meibergdreef 59, 1105 BA Amsterdam, The Netherlands.
authors.forename: Tim
authors.initials: T
authors.lastname: Beaumont
authors.affiliation: Department of Medical Microbiology, Laboratory of Clinical Virology, Academic Medical Center, Meibergdreef 9, 1105 Amsterdam, The Netherlands.
authors.forename: Katja C
authors.initials: KC
authors.lastname: Wolthers
authors.affiliation: Institute of Biotechnology and Department of Biological Sciences, Viikinkaari 1, 00014 University of Helsinki, Finland.
authors.forename: Sarah J
authors.identifier: 0000-0001-7060-5871
authors.initials: SJ
authors.lastname: Butcher
mesh_terms: D000595:Amino Acid Sequence; D002213:Capsid / Q000737:chemistry / Q000378:metabolism*; D036022:Capsid Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D018360:Crystallography, X-Ray; D006801:Humans; D008958:Models, Molecular; D008969:Molecular Sequence Data; D000071074:Neonatal Sepsis / Q000821:virology*; D030061:Parechovirus / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D010850:Picornaviridae Infections / Q000821:virology*; D011485:Protein Binding; D011487:Protein Conformation; D016415:Sequence Alignment; D019065:Virus Assembly
chemical_list: D036022:Capsid Proteins