Structural basis for suppression of a host antiviral response by influenza a virus

Kalyan Das, Li Chung Ma, Rong Xiao, Brian Radvansky, James Aramini, Li Zhao, Jesper Marklund, Rei Lin Kuo, Karen Y. Twu, Eddy Arnold*, Robert M. Krug, Gaetano T. Montelione

*Corresponding author for this work

Research output: Contribution to journalJournal Article peer-review

188 Scopus citations

Abstract

Influenza A viruses are responsible for seasonal epidemics and high mortality pandemics. A major function of the viral NS1A protein, a virulence factor, is the inhibition of the production of IFN-β mRNA and other antiviral mRNAs. The NS1A protein of the human influenza A/Udorn/72 (Ud) virus inhibits the production of these antiviral mRNAs by binding the cellular 30-kDa subunit of the cleavage and polyadenylation specificity factor (CPSF30), which is required for the 3′ end processing of all cellular pre-mRNAs. Here we report the 1.95-Å resolution X-ray crystal structure of the complex formed between the second and third zinc finger domain (F2F3) of CPSF30 and the C-terminal domain of the Ud NS1A protein. The complex is a tetramer, in which each of two F2F3 molecules wraps around two NS1A effector domains that interact with each other head-to-head. This structure identifies a CPSF30 binding pocket on NS1A comprised of amino acid residues that are highly conserved among human influenza A viruses. Single amino acid changes within this binding pocket eliminate CPSF30 binding, and a recombinant Ud virus expressing an NS1A protein with such a substitution is attenuated and does not inhibit IFN-β pre-mRNA processing. This binding pocket is a potential target for antiviral drug development. The crystal structure also reveals that two amino acids outside of this pocket, F103 and M106, which are highly conserved (>99%) among influenza A viruses isolated from humans, participate in key hydrophobic interactions with F2F3 that stabilize the complex.

Original languageEnglish
Pages (from-to)13093-13098
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume105
Issue number35
DOIs
StatePublished - 02 09 2008
Externally publishedYes

Keywords

  • Antiviral drug discovery
  • Bird flu
  • Vaccine engineering
  • Virology
  • X-ray crystallography

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