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

@article{citeulike:3193274, abstract = {10.1073/pnas.0805213105 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-\r{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-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.}, author = {Das, Kalyan and Ma, Li-Chung and Xiao, Rong and Radvansky, Brian and Aramini, James and Zhao, Li and Marklund, Jesper and Kuo, Rei-Lin and Twu, Karen Y. and Arnold, Eddy and Krug, Robert M. and Montelione, Gaetano T. }, citeulike-article-id = {3193274}, doi = {http://dx.doi.org/10.1073/pnas.0805213105}, journal = {Proceedings of the National Academy of Sciences}, keywords = {influenza, innate, interferon}, number = {35}, pages = {13093--13098}, posted-at = {2008-09-04 15:09:34}, priority = {2}, title = {Structural basis for suppression of a host antiviral response by influenza A virus}, url = {http://dx.doi.org/10.1073/pnas.0805213105}, volume = {105}, year = {2008} }

TY - JOUR ID - citeulike:3193274 L3 - citeulike-article-id:3193274 N2 - 10.1073/pnas.0805213105 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. IS - 35 JF - Proceedings of the National Academy of Sciences EP - 13098 TI - Structural basis for suppression of a host antiviral response by influenza A virus VL - 105 SP - 13093 KW - influenza KW - innate KW - interferon AU - Das, Kalyan AU - Ma, Li-Chung AU - Xiao, Rong AU - Radvansky, Brian AU - Aramini, James AU - Zhao, Li AU - Marklund, Jesper AU - Kuo, Rei-Lin AU - Twu, Karen AU - Arnold, Eddy AU - Krug, Robert AU - Montelione, Gaetano PY - 2008//02/ UR - http://dx.doi.org/10.1073/pnas.0805213105 ER -