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PDBsum entry 2rhk
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Viral protein/nuclear protein
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PDB id
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2rhk
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References listed in PDB file
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Key reference
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Title
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Structural basis for suppression of a host antiviral response by influenza a virus.
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Authors
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K.Das,
L.C.Ma,
R.Xiao,
B.Radvansky,
J.Aramini,
L.Zhao,
J.Marklund,
R.L.Kuo,
K.Y.Twu,
E.Arnold,
R.M.Krug,
G.T.Montelione.
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Ref.
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Proc Natl Acad Sci U S A, 2008,
105,
13093-13098.
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PubMed id
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Abstract
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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.
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