6u28
From Proteopedia
(Difference between revisions)
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==Crystal structure of 1918 NS1-ED W187A in complex with the p85-beta-iSH2 domain of human PI3K== | ==Crystal structure of 1918 NS1-ED W187A in complex with the p85-beta-iSH2 domain of human PI3K== | ||
| - | <StructureSection load='6u28' size='340' side='right'caption='[[6u28]]' scene=''> | + | <StructureSection load='6u28' size='340' side='right'caption='[[6u28]], [[Resolution|resolution]] 2.95Å' scene=''> |
== Structural highlights == | == Structural highlights == | ||
| - | <table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6U28 OCA]. For a <b>guided tour on the structure components</b> use [ | + | <table><tr><td colspan='2'>[[6u28]] is a 4 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] and [https://en.wikipedia.org/wiki/Influenza_A_virus_(A/Brevig_Mission/1/1918(H1N1)) Influenza A virus (A/Brevig Mission/1/1918(H1N1))]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6U28 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6U28 FirstGlance]. <br> |
| - | </td></tr><tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[ | + | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.95Å</td></tr> |
| + | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=6u28 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6u28 OCA], [https://pdbe.org/6u28 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6u28 RCSB], [https://www.ebi.ac.uk/pdbsum/6u28 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6u28 ProSAT]</span></td></tr> | ||
</table> | </table> | ||
| + | == Function == | ||
| + | [https://www.uniprot.org/uniprot/NS1_I18A0 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). | ||
| + | <div style="background-color:#fffaf0;"> | ||
| + | == Publication Abstract from PubMed == | ||
| + | The 1918 influenza A virus (IAV) caused the most severe flu pandemic in recorded human history. Nonstructural protein 1 (NS1) is an important virulence factor of the 1918 IAV. NS1 antagonizes host defense mechanisms through interactions with multiple host factors. One pathway by which NS1 increases virulence is through the activation of phosphoinositide 3-kinase (PI3K) by binding to its p85beta subunit. Here we present the mechanism underlying the molecular recognition of the p85beta subunit by 1918 NS1. Using X-ray crystallography, we determine the structure of 1918 NS1 complexed with p85beta of human PI3K. We find that the 1918 NS1 effector domain (1918 NS1(ED)) undergoes a conformational change to bind p85beta. Using NMR relaxation dispersion and molecular dynamics simulation, we identify that free 1918 NS1(ED) exists in a dynamic equilibrium between p85beta-binding-competent and -incompetent conformations in the submillisecond timescale. Moreover, we discover that NS1(ED) proteins of 1918 (H1N1) and Udorn (H3N2) strains exhibit drastically different conformational dynamics and binding kinetics to p85beta. These results provide evidence of strain-dependent conformational dynamics of NS1. Using kinetic modeling based on the experimental data, we demonstrate that 1918 NS1(ED) can result in the faster hijacking of p85beta compared to Ud NS1(ED), although the former has a lower affinity to p85beta than the latter. Our results suggest that the difference in binding kinetics may impact the competition with cellular antiviral responses for the activation of PI3K. We anticipate that our findings will increase the understanding of the strain-dependent behaviors of influenza NS1 proteins. | ||
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| + | Molecular recognition of a host protein by NS1 of pandemic and seasonal influenza A viruses.,Cho JH, Zhao B, Shi J, Savage N, Shen Q, Byrnes J, Yang L, Hwang W, Li P Proc Natl Acad Sci U S A. 2020 Mar 24;117(12):6550-6558. doi:, 10.1073/pnas.1920582117. Epub 2020 Mar 9. PMID:32152123<ref>PMID:32152123</ref> | ||
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| + | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | ||
| + | </div> | ||
| + | <div class="pdbe-citations 6u28" style="background-color:#fffaf0;"></div> | ||
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| + | ==See Also== | ||
| + | *[[Phosphoinositide 3-kinase 3D structures|Phosphoinositide 3-kinase 3D structures]] | ||
| + | == References == | ||
| + | <references/> | ||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
| + | [[Category: Homo sapiens]] | ||
[[Category: Large Structures]] | [[Category: Large Structures]] | ||
[[Category: Cho JH]] | [[Category: Cho JH]] | ||
Current revision
Crystal structure of 1918 NS1-ED W187A in complex with the p85-beta-iSH2 domain of human PI3K
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Categories: Homo sapiens | Large Structures | Cho JH | Li P | Savage N | Zhao B
