View source for 6euw


==Crystal structure of the cap-binding domain of the PB2 subunit of influenza A/H5N1 polymerase bound to an azaindazole inhibitor==
<StructureSection load='6euw' size='340' side='right' caption='[[6euw]], [[Resolution|resolution]] 1.00&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[6euw]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Influenza_a_virus_(a/duck/shantou/4610/2003(h5n1)) Influenza a virus (a/duck/shantou/4610/2003(h5n1))]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6EUW OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6EUW FirstGlance]. <br>
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=BYB:(2~{S},3~{S})-3-[[5-fluoranyl-2-(5-fluoranyl-1~{H}-pyrazolo[3,4-b]pyridin-3-yl)pyrimidin-4-yl]amino]bicyclo[2.2.2]octane-2-carboxylic+acid'>BYB</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene></td></tr>
<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">PB2 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=365107 Influenza A virus (A/duck/Shantou/4610/2003(H5N1))])</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=6euw FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6euw OCA], [http://pdbe.org/6euw PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6euw RCSB], [http://www.ebi.ac.uk/pdbsum/6euw PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6euw ProSAT]</span></td></tr>
</table>
<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 6euw" style="background-color:#fffaf0;"></div>
== References ==
<references/>
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</StructureSection>
[[Category: Cusack, S]]
[[Category: Gaudon, S]]
[[Category: Cap-binding domain]]
[[Category: Influenza rna-dependent rna polymerase]]
[[Category: Inhibitor]]
[[Category: Pb2 subunit]]
[[Category: Rna binding protein]]