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==Crystal structure of bat influenza A/H17N10 polymerase with viral RNA promoter and cap analogue m7GTP== | |||
<StructureSection load='6evk' size='340' side='right' caption='[[6evk]], [[Resolution|resolution]] 2.90Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[6evk]] is a 5 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6EVK OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6EVK FirstGlance]. <br> | |||
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=MGP:7-METHYL-GUANOSINE-5-TRIPHOSPHATE'>MGP</scene>, <scene name='pdbligand=PO4:PHOSPHATE+ION'>PO4</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></td></tr> | |||
<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/RNA-directed_RNA_polymerase RNA-directed RNA polymerase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.7.48 2.7.7.48] </span></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=6evk FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6evk OCA], [http://pdbe.org/6evk PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6evk RCSB], [http://www.ebi.ac.uk/pdbsum/6evk PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6evk 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> | |||
[[Category: | </div> | ||
<div class="pdbe-citations 6evk" style="background-color:#fffaf0;"></div> | |||
== References == | |||
<references/> | |||
__TOC__ | |||
</StructureSection> | |||
[[Category: RNA-directed RNA polymerase]] | |||
[[Category: Cusack, S]] | |||
[[Category: Pflug, A]] | [[Category: Pflug, A]] | ||
[[Category: | [[Category: Cap analogue]] | ||
[[Category: Influenza virus]] | |||
[[Category: Rna-dependent rna polymerase]] | |||
[[Category: Viral protein]] | |||
Revision as of 10:06, 13 December 2017
Crystal structure of bat influenza A/H17N10 polymerase with viral RNA promoter and cap analogue m7GTPCrystal structure of bat influenza A/H17N10 polymerase with viral RNA promoter and cap analogue m7GTP
Structural highlights
Publication Abstract from PubMedInfluenza 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[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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