6euw: Difference between revisions
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==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]] 1.00Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[6euw]] is a 1 chain structure. 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='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®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
<div class="pdbe-citations 6euw" style="background-color:#fffaf0;"></div> | |||
== References == | |||
<references/> | |||
__TOC__ | |||
</StructureSection> | |||
[[Category: Cusack, S]] | [[Category: Cusack, S]] | ||
[[Category: Gaudon, S]] | [[Category: Gaudon, S]] | ||
[[Category: Cap-binding domain]] | |||
[[Category: Influenza rna-dependent rna polymerase]] | |||
[[Category: Inhibitor]] | |||
[[Category: Pb2 subunit]] | |||
[[Category: Rna binding protein]] | |||
Revision as of 07:06, 13 December 2017
Crystal structure of the cap-binding domain of the PB2 subunit of influenza A/H5N1 polymerase bound to an azaindazole inhibitor
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