4nce: Difference between revisions
New page: '''Unreleased structure''' The entry 4nce is ON HOLD Authors: Jacobs, M.D. Description: Influenza polymerase basic protein 2 (PB2) bound to 7-methyl-GTP |
No edit summary |
||
| (7 intermediate revisions by the same user not shown) | |||
| Line 1: | Line 1: | ||
==Influenza polymerase basic protein 2 (PB2) bound to 7-methyl-GTP== | |||
<StructureSection load='4nce' size='340' side='right'caption='[[4nce]], [[Resolution|resolution]] 2.30Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[4nce]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Influenza_A_virus_(A/Victoria/3/1975(H3N2)) Influenza A virus (A/Victoria/3/1975(H3N2))]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4NCE OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4NCE FirstGlance]. <br> | |||
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.3Å</td></tr> | |||
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=11H:9,10-DIOXO-9,10-DIHYDROANTHRACENE-2,6-DISULFONIC+ACID'>11H</scene>, <scene name='pdbligand=MGT:7N-METHYL-8-HYDROGUANOSINE-5-TRIPHOSPHATE'>MGT</scene></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=4nce FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4nce OCA], [https://pdbe.org/4nce PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4nce RCSB], [https://www.ebi.ac.uk/pdbsum/4nce PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4nce ProSAT]</span></td></tr> | |||
</table> | |||
== Function == | |||
[https://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 == | |||
In our effort to develop agents for the treatment of influenza, a phenotypic screening approach utilizing a cell protection assay identified a series of azaindole based inhibitors of the cap-snatching function of the PB2 subunit of the influenza A viral polymerase complex. Using a bDNA viral replication assay ( Wagaman , P. C. , Leong , M. A. , and Simmen , K. A. Development of a novel influenza A antiviral assay . J. Virol. Methods 2002 , 105 , 105 - 114 ) in cells as a direct measure of antiviral activity, we discovered a set of cyclohexyl carboxylic acid analogues, highlighted by VX-787 (2). Compound 2 shows strong potency versus multiple influenza A strains, including pandemic 2009 H1N1 and avian H5N1 flu strains, and shows an efficacy profile in a mouse influenza model even when treatment was administered 48 h after infection. Compound 2 represents a first-in-class, orally bioavailable, novel compound that offers potential for the treatment of both pandemic and seasonal influenza and has a distinct advantage over the current standard of care treatments including potency, efficacy, and extended treatment window. | |||
Discovery of a Novel, First-in-Class, Orally Bioavailable Azaindole Inhibitor (VX-787) of Influenza PB2.,Clark MP, Ledeboer MW, Davies I, Byrn RA, Jones SM, Perola E, Tsai A, Jacobs M, Nti-Addae K, Bandarage UK, Boyd MJ, Bethiel RS, Court JJ, Deng H, Duffy JP, Dorsch WA, Farmer LJ, Gao H, Gu W, Jackson K, Jacobs DH, Kennedy JM, Ledford B, Liang J, Maltais F, Murcko M, Wang T, Wannamaker MW, Bennett HB, Leeman JR, McNeil C, Taylor WP, Memmott C, Jiang M, Rijnbrand R, Bral C, Germann U, Nezami A, Zhang Y, Salituro FG, Bennani YL, Charifson PS J Med Chem. 2014 Jul 24. PMID:25019388<ref>PMID:25019388</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
<div class="pdbe-citations 4nce" style="background-color:#fffaf0;"></div> | |||
==See Also== | |||
*[[RNA polymerase 3D structures|RNA polymerase 3D structures]] | |||
== References == | |||
<references/> | |||
__TOC__ | |||
</StructureSection> | |||
[[Category: Large Structures]] | |||
[[Category: Jacobs MD]] | |||
Latest revision as of 19:53, 20 September 2023
Influenza polymerase basic protein 2 (PB2) bound to 7-methyl-GTPInfluenza polymerase basic protein 2 (PB2) bound to 7-methyl-GTP
Structural highlights
FunctionPB2_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 PubMedIn our effort to develop agents for the treatment of influenza, a phenotypic screening approach utilizing a cell protection assay identified a series of azaindole based inhibitors of the cap-snatching function of the PB2 subunit of the influenza A viral polymerase complex. Using a bDNA viral replication assay ( Wagaman , P. C. , Leong , M. A. , and Simmen , K. A. Development of a novel influenza A antiviral assay . J. Virol. Methods 2002 , 105 , 105 - 114 ) in cells as a direct measure of antiviral activity, we discovered a set of cyclohexyl carboxylic acid analogues, highlighted by VX-787 (2). Compound 2 shows strong potency versus multiple influenza A strains, including pandemic 2009 H1N1 and avian H5N1 flu strains, and shows an efficacy profile in a mouse influenza model even when treatment was administered 48 h after infection. Compound 2 represents a first-in-class, orally bioavailable, novel compound that offers potential for the treatment of both pandemic and seasonal influenza and has a distinct advantage over the current standard of care treatments including potency, efficacy, and extended treatment window. Discovery of a Novel, First-in-Class, Orally Bioavailable Azaindole Inhibitor (VX-787) of Influenza PB2.,Clark MP, Ledeboer MW, Davies I, Byrn RA, Jones SM, Perola E, Tsai A, Jacobs M, Nti-Addae K, Bandarage UK, Boyd MJ, Bethiel RS, Court JJ, Deng H, Duffy JP, Dorsch WA, Farmer LJ, Gao H, Gu W, Jackson K, Jacobs DH, Kennedy JM, Ledford B, Liang J, Maltais F, Murcko M, Wang T, Wannamaker MW, Bennett HB, Leeman JR, McNeil C, Taylor WP, Memmott C, Jiang M, Rijnbrand R, Bral C, Germann U, Nezami A, Zhang Y, Salituro FG, Bennani YL, Charifson PS J Med Chem. 2014 Jul 24. PMID:25019388[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
|
| ||||||||||||||||||