Structural Basis for Suppression of a Host Antiviral Response by Influenza A Virus

Journal Article · Tue Jan 01 04:00:00 EST 2008 · Proceedings of the National Academy of Sciences of the USA

DOI:https://doi.org/10.1073/pnas.0805213105· OSTI ID:959473

Das, K; Ma, L; Xiao, R; Radvansky, B; Aramini, J; Zhao, L; Marklund, J; Kuo, R; Twu, K; Arnold, E

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}{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- Angstroms 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.

• Research Organization: Brookhaven National Laboratory (BNL) National Synchrotron Light Source
• Sponsoring Organization: Doe - Office Of Science
• DOE Contract Number: AC02-98CH10886
• OSTI ID: 959473
• Report Number(s): BNL--82459-2009-JA
• Journal Information: Proceedings of the National Academy of Sciences of the USA, Journal Name: Proceedings of the National Academy of Sciences of the USA Journal Issue: 35 Vol. 105; ISSN PNASA6; ISSN 0027-8424
• Country of Publication: United States
• Language: English

Related Subjects

36 MATERIALS SCIENCE
AMINO ACIDS
CLEAVAGE
CRYSTAL STRUCTURE
FINGERS
INFLUENZA
MORTALITY
PROCESSING
PRODUCTION
PROTEINS
RESIDUES
RESOLUTION
SPECIFICITY
TARGETS
VIRULENCE
VIRUSES
ZINC
national synchrotron light source