title: Structure of importin-α bound to a non-classical nuclear localization signal of the influenza A virus nucleoprotein.
abstract: A non-classical nuclear localization signal (ncNLS) of influenza A virus nucleoprotein (NP) is critical for nuclear import of viral genomic RNAs that transcribe and replicate in the nucleus of infected cells. Here we report a 2.3 Å resolution crystal structure of mouse importin-α1 in complex with NP ncNLS. The structure reveals that NP ncNLS binds specifically and exclusively to the minor NLS-binding site of importin-α. Structural and functional analyses identify key binding pockets on importin-α as potential targets for antiviral drug development. Unlike many other NLSs, NP ncNLS binds to the NLS-binding domain of importin-α weakly with micromolar affinity. These results suggest that a modest inhibitor with low affinity to importin-α could have anti-influenza activity with minimal cytotoxicity.
authors.affiliation: Division of Biological Science Graduate School of Science Nagoya University Japan.
authors.forename: Ryohei
authors.initials: R
authors.lastname: Nakada
authors.affiliation: Division of Biological Science Graduate School of Science Nagoya University Japan.
authors.forename: Hidemi
authors.initials: H
authors.lastname: Hirano
authors.affiliation: Division of Biological Science Graduate School of Science Nagoya University Japan.|Structural Biology Research Center, Graduate School of Science, Nagoya University, Japan.
authors.forename: Yoshiyuki
authors.initials: Y
authors.lastname: Matsuura
mesh_terms: D021581:Active Transport, Cell Nucleus; D000818:Animals; D001665:Binding Sites; D002467:Cell Nucleus / Q000378:metabolism; D018360:Crystallography, X-Ray; D004926:Escherichia coli / Q000235:genetics / Q000378:metabolism; D015870:Gene Expression; D054884:Host-Pathogen Interactions; D007700:Kinetics; D051379:Mice; D008958:Models, Molecular; D008969:Molecular Sequence Data; D041681:NIH 3T3 Cells; D019913:Nuclear Localization Signals; D019590:Nucleocapsid Proteins; D011485:Protein Binding; D054730:Protein Interaction Domains and Motifs; D017433:Protein Structure, Secondary; D016601:RNA-Binding Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D014758:Viral Core Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D028901:alpha Karyopherins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism
chemical_list: C048842:NP protein, Influenza A virus; D019913:Nuclear Localization Signals; D019590:Nucleocapsid Proteins; D016601:RNA-Binding Proteins; D011994:Recombinant Proteins; D014758:Viral Core Proteins; D028901:alpha Karyopherins