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

Research output: Contribution to journalArticlepeer-review

186 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 (US)
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 - Sep 2 2008

All Science Journal Classification (ASJC) codes

  • General

Keywords

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

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