6dgk | pdb_00006dgk
Crystal Structure of the Non-Structural Protein 1 (NS1) effector domain W187A mutant from the A/Brevig Mission/1/1918 (H1N1) strain of Influenza A Virus
Structural highlights
Function[NS1_I18A0] 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 (By similarity). 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). Publication Abstract from PubMedThe influenza virus is a significant public health concern causing 250,000-500,000 deaths worldwide each year. Its ability to change quickly results in the potential for rapid generation of pandemic strains for which most individuals would have no antibody protection. This pandemic potential highlights the need for the continuous development of new drugs against influenza virus. As an essential component, and well-established virulence determinant, the non-structural protein 1 (NS1) of influenza virus is a highly prioritized target for the development of anti-influenza compounds. Here, we used NMR to determine that the NS1 effector domain (NS1(ED)) derived from the A/Brevig Mission/1/1918 (H1N1) strain of influenza (1918(H1N1)) binds to two previously described anti-influenza compounds A9 (JJ3297) and A22. We then used X-ray crystallography to determine the three-dimensional structure of the 1918(H1N1) NS1(ED) Furthermore, we mapped the A9/A22-binding site onto our 1918(H1N1) NS1(ED) structure and determined that A9 and A22 interact with the NS1(ED) in the hydrophobic pocket known to facilitate binding to the 30 kDa subunit of the cleavage and polyadenylation specificity factor (CPSF30), suggesting that the two compounds likely attenuate influenza replication by inhibiting the NS1(ED)-CPSF30 interaction. Finally, our structure revealed that NS1(ED) could dimerize via an interface that we termed the alpha3-alpha3 dimer. Taken together, the findings presented here provide strong evidence for the mechanism of action of two anti-influenza compounds that target NS1 and contribute significant structural insights into NS1 that we hope will promote and inform the development and optimization of influenza therapies based on A9/A22. Structural analyses reveal the mechanism of inhibition of influenza virus NS1 by two antiviral compounds.,Kleinpeter AB, Jureka AS, Falahat SM, Green TJ, Petit CM J Biol Chem. 2018 Aug 3. pii: RA118.004012. doi: 10.1074/jbc.RA118.004012. PMID:30076219[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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