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2rhk

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Revision as of 07:12, 10 June 2020

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

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:	, ,
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.^[1] ^[2] ^[3] 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).^[4] ^[5] ^[6] [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).^[7] ^[8]

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^[9]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Nemeroff ME, Barabino SM, Li Y, Keller W, Krug RM. Influenza virus NS1 protein interacts with the cellular 30 kDa subunit of CPSF and inhibits 3'end formation of cellular pre-mRNAs. Mol Cell. 1998 Jun;1(7):991-1000. PMID:9651582
↑ Li Y, Yamakita Y, Krug RM. Regulation of a nuclear export signal by an adjacent inhibitory sequence: the effector domain of the influenza virus NS1 protein. Proc Natl Acad Sci U S A. 1998 Apr 28;95(9):4864-9. PMID:9560194
↑ Twu KY, Noah DL, Rao P, Kuo RL, Krug RM. The CPSF30 binding site on the NS1A protein of influenza A virus is a potential antiviral target. J Virol. 2006 Apr;80(8):3957-65. PMID:16571812 doi:10.1128/JVI.80.8.3957-3965.2006
↑ Nemeroff ME, Barabino SM, Li Y, Keller W, Krug RM. Influenza virus NS1 protein interacts with the cellular 30 kDa subunit of CPSF and inhibits 3'end formation of cellular pre-mRNAs. Mol Cell. 1998 Jun;1(7):991-1000. PMID:9651582
↑ Li Y, Yamakita Y, Krug RM. Regulation of a nuclear export signal by an adjacent inhibitory sequence: the effector domain of the influenza virus NS1 protein. Proc Natl Acad Sci U S A. 1998 Apr 28;95(9):4864-9. PMID:9560194
↑ Twu KY, Noah DL, Rao P, Kuo RL, Krug RM. The CPSF30 binding site on the NS1A protein of influenza A virus is a potential antiviral target. J Virol. 2006 Apr;80(8):3957-65. PMID:16571812 doi:10.1128/JVI.80.8.3957-3965.2006
↑ Barabino SM, Hubner W, Jenny A, Minvielle-Sebastia L, Keller W. The 30-kD subunit of mammalian cleavage and polyadenylation specificity factor and its yeast homolog are RNA-binding zinc finger proteins. Genes Dev. 1997 Jul 1;11(13):1703-16. PMID:9224719
↑ Kaufmann I, Martin G, Friedlein A, Langen H, Keller W. Human Fip1 is a subunit of CPSF that binds to U-rich RNA elements and stimulates poly(A) polymerase. EMBO J. 2004 Feb 11;23(3):616-26. Epub 2004 Jan 29. PMID:14749727 doi:http://dx.doi.org/10.1038/sj.emboj.7600070
↑ Das K, Ma LC, Xiao R, Radvansky B, Aramini J, Zhao L, Marklund J, Kuo RL, Twu KY, Arnold E, Krug RM, Montelione GT. Structural basis for suppression of a host antiviral response by influenza A virus. Proc Natl Acad Sci U S A. 2008 Sep 2;105(35):13093-8. Epub 2008 Aug 25. PMID:18725644

1 Structural highlights
2 Function
3 Evolutionary Conservation
4 Publication Abstract from PubMed
5 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/2rhk"

@@ Line 1: / Line 1: @@
 ==Crystal structure of influenza A NS1A protein in complex with F2F3 fragment of human cellular factor CPSF30, Northeast Structural Genomics Targets OR8C and HR6309A==
-<StructureSection load='2rhk' size='340' side='right' caption='[[2rhk]], [[Resolution|resolution]] 1.95&Aring;' scene=''>
+<StructureSection load='2rhk' size='340' side='right'caption='[[2rhk]], [[Resolution|resolution]] 1.95&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[2rhk]] is a 4 chain structure with sequence from [http://en.wikipedia.org/wiki/9infa 9infa] and [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2RHK OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=2RHK FirstGlance]. <br>
+<table><tr><td colspan='2'>[[2rhk]] is a 4 chain structure with sequence from [http://en.wikipedia.org/wiki/9infa 9infa] and [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2RHK OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=2RHK FirstGlance]. <br>
-</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=NO3:NITRATE+ION'>NO3</scene>, <scene name='pdbligand=TRS:2-AMINO-2-HYDROXYMETHYL-PROPANE-1,3-DIOL'>TRS</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></td></tr>
+</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=NO3:NITRATE+ION'>NO3</scene>, <scene name='pdbligand=TRS:2-AMINO-2-HYDROXYMETHYL-PROPANE-1,3-DIOL'>TRS</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></td></tr>
 <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[2d9n|2d9n]], [[2gx9|2gx9]]</td></tr>
-<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=2rhk FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2rhk OCA], [http://pdbe.org/2rhk PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=2rhk RCSB], [http://www.ebi.ac.uk/pdbsum/2rhk PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=2rhk ProSAT]</span></td></tr>
+<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://proteopedia.org/fgij/fg.htm?mol=2rhk FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2rhk OCA], [http://pdbe.org/2rhk PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=2rhk RCSB], [http://www.ebi.ac.uk/pdbsum/2rhk PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=2rhk ProSAT]</span></td></tr>
 </table>
 == Function ==
@@ Line 34: / Line 34: @@
 </StructureSection>
 [[Category: Human]]
+[[Category: Large Structures]]
 [[Category: Aramini, J]]
 [[Category: Arnold, E]]

2rhk

From Proteopedia

Revision as of 07:12, 10 June 2020

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

Structural highlights

Function

Evolutionary Conservation

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

Views

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