2RHK

Crystal structure of influenza A NS1A protein in complex with F2F3 fragment of human cellular factor CPSF30, Northeast Structural Genomics Targets OR8C and HR6309A

Summary for 2RHK

• Entry DOI: 10.2210/pdb2rhk/pdb
• Related: 2D9N 2GX9
• Descriptor: Non-structural protein 1, Cleavage and polyadenylation specificity factor subunit 4, NITRATE ION, ... (6 entities in total)
• Functional Keywords: influenza a, nonstructural protein, viral protein: host complex, zn finger, alternative splicing, cytoplasm, host-virus interaction, interferon antiviral system evasion, nucleus, rna-binding, suppressor of rna silencing, metal-binding, mrna processing, zinc, zinc-finger, metal binding protein, viral protein-metal binding protein complex, viral protein-nuclear protein complex, structural genomics, psi-2, protein structure initiative, northeast structural genomics consortium, nesg, viral protein/nuclear protein
• Biological source: Influenza A Virus; More
• Cellular location: Host nucleus: P03495; Nucleus: O95639
• Total number of polymer chains: 4
• Total formula weight: 49764.23

Authors

Das, K.,Ma, L.-C.,Xiao, R.,Radvansky, B.,Aramini, J.,Zhao, L.,Arnold, E.,Krug, R.M.,Montelione, G.T.,Northeast Structural Genomics Consortium (NESG) (deposition date: 2007-10-09, release date: 2008-07-01, Last modification date: 2024-02-21)

Primary citation

Das, K.,Ma, L.C.,Xiao, R.,Radvansky, B.,Aramini, J.,Zhao, L.,Marklund, J.,Kuo, R.L.,Twu, K.Y.,Arnold, E.,Krug, R.M.,Montelione, G.T.
Structural basis for suppression of a host antiviral response by influenza A virus.
Proc.Natl.Acad.Sci.Usa, 105:13093-13098, 2008

PubMed 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.

PubMed: 18725644
DOI: 10.1073/pnas.0805213105

Experimental method

X-RAY DIFFRACTION (1.95 Å)