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

spinqualitylabelsall models 2rhk, resolution 1.95Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 2rhk is a 4 chain structure with sequence from 9infa and Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Ligands: NO3, TRS, ZN Related: 2d9n, 2gx9 Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function [NS1_I72A2] Inhibits post-transcriptional processing of cellular pre-mRNA, by binding and inhibiting two cellular proteins that are required for the 3'-end processing of cellular pre-mRNAs: the 30 kDa cleavage and polyadenylation specificity factor (CPSF4) and the poly(A)-binding protein 2 (PABPN1). This results in the accumulation of unprocessed 3' end pre-mRNAs which can't be exported from the nucleus. Cellular protein synthesis is thereby shut off very early after virus infection. Viral protein synthesis is not affected by the inhibition of the cellular 3' end processing machinery because the poly(A) tails of viral mRNAs are produced by the viral polymerase through a stuttering mechanism. Prevents the establishment of the cellular antiviral state by inhibiting TRIM25-mediated DDX58 ubiquitination, which normally triggers the antiviral transduction signal that leads to the activation of type I IFN genes by transcription factors like IRF3 and IRF7. Prevents human EIF2AK2/PKR activation, either by binding double-strand RNA, or by interacting directly with EIF2AK2/PKR. This function may be important at the very beginning of the infection, when NS1 is mainly present in the cytoplasm. Also binds poly(A) and U6 snRNA. Suppresses the RNA silencing-based antiviral response in Drosophila cells (By similarity). [CPSF4_HUMAN] Component of the cleavage and polyadenylation specificity factor (CPSF) complex that play a key role in pre-mRNA 3'-end formation, recognizing the AAUAAA signal sequence and interacting with poly(A) polymerase and other factors to bring about cleavage and poly(A) addition. CPSF4 binds RNA polymers with a preference for poly(U). Evolutionary Conservation Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf. Publication Abstract from PubMed 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. Structural basis for suppression of a host antiviral response by influenza A virus.,Das K, Ma LC, Xiao R, Radvansky B, Aramini J, Zhao L, Marklund J, Kuo RL, Twu KY, Arnold E, Krug RM, Montelione GT Proc Natl Acad Sci U S A. 2008 Sep 2;105(35):13093-8. Epub 2008 Aug 25. PMID:18725644 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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