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

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-beta 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-A 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-beta 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.

• Authors: 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
• Journal: Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 105 Issue 35 Pg. 13093-8 (Sep 02 2008) ISSN: 1091-6490 [Electronic] United States
• PMID: 18725644 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Interferon Regulatory Factor-3
• Viral Nonstructural Proteins
• Phenylalanine
• Methionine

Topics

• Amino Acid Substitution
• Binding Sites
• Cell Line
• Crystallography, X-Ray
• Humans
• Influenza A virus (chemistry, immunology)
• Interferon Regulatory Factor-3 (metabolism)
• Methionine (metabolism)
• Models, Molecular
• Phenylalanine (metabolism)
• Protein Structure, Quaternary
• Protein Structure, Secondary
• Thermodynamics
• Viral Nonstructural Proteins (chemistry, metabolism)
• Zinc Fingers