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| | <StructureSection load='4yd0' size='340' side='right'caption='[[4yd0]], [[Resolution|resolution]] 2.62Å' scene=''> | | <StructureSection load='4yd0' size='340' side='right'caption='[[4yd0]], [[Resolution|resolution]] 2.62Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[4yd0]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/I75a0 I75a0]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4YD0 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4YD0 FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[4yd0]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Influenza_A_virus_(A/Beijing/39/1975(H3N2)) Influenza A virus (A/Beijing/39/1975(H3N2))]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4YD0 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4YD0 FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=4EW:2-(5-CHLORO-1H-PYRROLO[2,3-B]PYRIDIN-3-YL)-5-FLUORO-N-[(1R,2S,3S,4R)-3-(1H-TETRAZOL-5-YL)BICYCLO[2.2.2]OCT-2-YL]PYRIMIDIN-4-AMINE'>4EW</scene></td></tr> | + | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=4EW:2-(5-CHLORO-1H-PYRROLO[2,3-B]PYRIDIN-3-YL)-5-FLUORO-N-[(1R,2S,3S,4R)-3-(1H-TETRAZOL-5-YL)BICYCLO[2.2.2]OCT-2-YL]PYRIMIDIN-4-AMINE'>4EW</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=383596 I75A0])</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=4yd0 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4yd0 OCA], [https://pdbe.org/4yd0 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4yd0 RCSB], [https://www.ebi.ac.uk/pdbsum/4yd0 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4yd0 ProSAT]</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=4yd0 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4yd0 OCA], [http://pdbe.org/4yd0 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4yd0 RCSB], [http://www.ebi.ac.uk/pdbsum/4yd0 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4yd0 ProSAT]</span></td></tr> | + | |
| | </table> | | </table> |
| | == Function == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/PB2_I75A0 PB2_I75A0]] Plays an essential role in transcription initiation and cap-stealing mechanism, in which cellular capped pre-mRNAs are used to generate primers for viral transcription. Binds the cap of the target pre-RNA which is subsequently cleaved after 10-13 nucleotides by PA. Plays a role in the initiation of the viral genome replication and modulates the activity of the ribonucleoprotein (RNP) complex. In addition, participates in the inhibition of type I interferon induction through interaction with the host mitochondrial antiviral signaling protein MAVS.[UniProtKB:P03428] | + | [https://www.uniprot.org/uniprot/PB2_I75A0 PB2_I75A0] Plays an essential role in transcription initiation and cap-stealing mechanism, in which cellular capped pre-mRNAs are used to generate primers for viral transcription. Binds the cap of the target pre-RNA which is subsequently cleaved after 10-13 nucleotides by PA. Plays a role in the initiation of the viral genome replication and modulates the activity of the ribonucleoprotein (RNP) complex. In addition, participates in the inhibition of type I interferon induction through interaction with the host mitochondrial antiviral signaling protein MAVS.[UniProtKB:P03428] |
| | <div style="background-color:#fffaf0;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
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| | | | |
| | ==See Also== | | ==See Also== |
| - | *[[RNA polymerase|RNA polymerase]] | + | *[[RNA polymerase 3D structures|RNA polymerase 3D structures]] |
| | == References == | | == References == |
| | <references/> | | <references/> |
| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: I75a0]] | |
| | [[Category: Large Structures]] | | [[Category: Large Structures]] |
| - | [[Category: Jacobs, M D]] | + | [[Category: Jacobs MD]] |
| - | [[Category: Flu]]
| + | |
| - | [[Category: Inhibitor]]
| + | |
| - | [[Category: M7-gtp pocket]]
| + | |
| - | [[Category: Small-molecule drug]]
| + | |
| - | [[Category: Transcription-inhibitor complex]]
| + | |
| Structural highlights
Function
PB2_I75A0 Plays an essential role in transcription initiation and cap-stealing mechanism, in which cellular capped pre-mRNAs are used to generate primers for viral transcription. Binds the cap of the target pre-RNA which is subsequently cleaved after 10-13 nucleotides by PA. Plays a role in the initiation of the viral genome replication and modulates the activity of the ribonucleoprotein (RNP) complex. In addition, participates in the inhibition of type I interferon induction through interaction with the host mitochondrial antiviral signaling protein MAVS.[UniProtKB:P03428]
Publication Abstract from PubMed
VX-787 is a first in class, orally bioavailable compound that offers unparalleled potential for the treatment of pandemic and seasonal influenza. As a part of our routine SAR exploration, carboxylic acid isosteres of VX-787 were prepared and tested against influenza A. It was found that the negative charge is important for maintaining potency and selectivity relative to kinase targets. Neutral carboxylic acid replacements generally resulted in compounds that were significantly less potent and less selective relative to the charged species.
Isosteric replacements of the carboxylic acid of drug candidate VX-787: Effect of charge on antiviral potency and kinase activity of azaindole-based influenza PB2 inhibitors.,Boyd MJ, Bandarage UK, Bennett H, Byrn RR, Davies I, Gu W, Jacobs M, Ledeboer MW, Ledford B, Leeman JR, Perola E, Wang T, Bennani Y, Clark MP, Charifson PS Bioorg Med Chem Lett. 2015 Mar 14. pii: S0960-894X(15)00209-7. doi:, 10.1016/j.bmcl.2015.03.013. PMID:25827523[1]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Boyd MJ, Bandarage UK, Bennett H, Byrn RR, Davies I, Gu W, Jacobs M, Ledeboer MW, Ledford B, Leeman JR, Perola E, Wang T, Bennani Y, Clark MP, Charifson PS. Isosteric replacements of the carboxylic acid of drug candidate VX-787: Effect of charge on antiviral potency and kinase activity of azaindole-based influenza PB2 inhibitors. Bioorg Med Chem Lett. 2015 Mar 14. pii: S0960-894X(15)00209-7. doi:, 10.1016/j.bmcl.2015.03.013. PMID:25827523 doi:http://dx.doi.org/10.1016/j.bmcl.2015.03.013
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