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==Structure of the midlink and cap-binding domains of influenza A polymerase PB2 subunit with a bound azaindole cap-binding inhibitor (VX-787)==
<StructureSection load='6euv' size='340' side='right'caption='[[6euv]], [[Resolution|resolution]] 2.70&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[6euv]] is a 4 chain structure with sequence from [https://en.wikipedia.org/wiki/Influenza_A_virus_(A/Victoria/3/1975(H3N2)) Influenza A virus (A/Victoria/3/1975(H3N2))]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6EUV OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6EUV FirstGlance]. <br>
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.7&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=21G:(2S,3S)-3-[[5-FLUORANYL-2-(5-FLUORANYL-1H-PYRROLO[2,3-B]PYRIDIN-3-YL)PYRIMIDIN-4-YL]AMINO]BICYCLO[2.2.2]OCTANE-2-CARBOXYLIC+ACID'>21G</scene>, <scene name='pdbligand=NI:NICKEL+(II)+ION'>NI</scene></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=6euv FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6euv OCA], [https://pdbe.org/6euv PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6euv RCSB], [https://www.ebi.ac.uk/pdbsum/6euv PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6euv ProSAT]</span></td></tr>
</table>
== Function ==
[https://www.uniprot.org/uniprot/PB2_I75A3 PB2_I75A3] Involved in transcription initiation and cap-stealing mechanism, in which cellular capped pre-mRNA are used to generate primers for viral transcription. Binds the cap of the target pre-RNA which is subsequently cleaved by PB1. May play a role in genome replication (By similarity).
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
Influenza polymerase uses short capped primers snatched from nascent Pol II transcripts to initiate transcription of viral mRNAs. Here we describe crystal structures of influenza A and B polymerase bound to a capped primer in a configuration consistent with transcription initiation ('priming state') and show by functional assays that conserved residues from both the PB2 midlink and cap-binding domains are important for positioning the capped RNA. In particular, mutation of PB2 Arg264, which interacts with the triphosphate linkage in the cap, significantly and specifically decreases cap-dependent transcription. We also compare the configuration of the midlink and cap-binding domains in the priming state with their very different relative arrangement (called the 'apo' state) in structures where the potent cap-binding inhibitor VX-787, or a close analogue, is bound. In the 'apo' state the inhibitor makes additional interactions to the midlink domain that increases its affinity beyond that to the cap-binding domain alone. The comparison suggests that the mechanism of resistance of certain mutations that allow virus to escape from VX-787, notably PB2 N510T, can only be rationalized if VX-787 has a dual mode of action, direct inhibition of capped RNA binding as well as stabilization of the transcriptionally inactive 'apo' state.

Capped RNA primer binding to influenza polymerase and implications for the mechanism of cap-binding inhibitors.,Pflug A, Gaudon S, Resa-Infante P, Lethier M, Reich S, Schulze WM, Cusack S Nucleic Acids Res. 2017 Nov 30. pii: 4675317. doi: 10.1093/nar/gkx1210. PMID:29202182<ref>PMID:29202182</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 6euv" style="background-color:#fffaf0;"></div>

==See Also==
*[[RNA polymerase 3D structures|RNA polymerase 3D structures]]
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Large Structures]]
[[Category: Cusack S]]
[[Category: Lethier M]]