6euv: Difference between revisions

Line 1:

~~'''Unreleased structure'''~~

~~The entry~~ 6euv is ~~ON HOLD until Paper~~ Publication

==Structure of the midlink and cap-binding domains of influenza A polymerase PB2 subunit with a bound azaindole cap-binding inhibitor (VX-787)==

== Structural highlights ==

<table><tr><td colspan='2'>[[6euv]] is a 4 chain structure. 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 [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6EUV FirstGlance]. <br>

</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><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'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6euv FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6euv OCA], [http://pdbe.org/6euv PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6euv RCSB], [http://www.ebi.ac.uk/pdbsum/6euv PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6euv ProSAT]</span></td></tr>

</table>

== Function ==

[[http://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).

== 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.

~~Authors: Cusack~~, S., Lethier, M.

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>

~~Description: Structure~~ of the ~~midlink and cap-binding domains~~ of ~~influenza A polymerase PB2 subunit with a bound azaindole cap~~-~~binding inhibitor (VX~~-~~787)~~

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

[[Category: ~~Unreleased Structures~~]]

</div>

== References ==

__TOC__

</StructureSection>

[[Category: Cusack, S]]

[[Category: Lethier, M]]

[[Category: ~~Cusack, S~~]]

[[Category: Cap-binding domain]]

[[Category: Cap-binding inhibitor]]

[[Category: Influenza a polymerase]]

[[Category: Pb2 subunit]]

[[Category: Rna binding protein]]

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@@ Line 1: / Line 1: @@
-'''Unreleased structure'''
-The entry 6euv is ON HOLD  until Paper Publication
+==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. 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 [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6EUV FirstGlance]. <br>
+</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><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'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6euv FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6euv OCA], [http://pdbe.org/6euv PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6euv RCSB], [http://www.ebi.ac.uk/pdbsum/6euv PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6euv ProSAT]</span></td></tr>
+</table>
+== Function ==
+[[http://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.
-Authors: Cusack, S., Lethier, M.
+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>
-Description: Structure of the midlink and cap-binding domains of influenza A polymerase PB2 subunit with a bound azaindole cap-binding inhibitor (VX-787)
+From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
-[[Category: Unreleased Structures]]
+</div>
+<div class="pdbe-citations 6euv" style="background-color:#fffaf0;"></div>
+== References ==
+<references/>
+__TOC__
+</StructureSection>
+[[Category: Cusack, S]]
 [[Category: Lethier, M]]
-[[Category: Cusack, S]]
+[[Category: Cap-binding domain]]
+[[Category: Cap-binding inhibitor]]
+[[Category: Influenza a polymerase]]
+[[Category: Pb2 subunit]]
+[[Category: Rna binding protein]]