4yyl: Difference between revisions
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==Phenolic acid derivative bound to influenza strain H1N1 polymerase subunit PA endonuclease== | ==Phenolic acid derivative bound to influenza strain H1N1 polymerase subunit PA endonuclease== | ||
<StructureSection load='4yyl' size='340' side='right' caption='[[4yyl]], [[Resolution|resolution]] 1.91Å' scene=''> | <StructureSection load='4yyl' size='340' side='right'caption='[[4yyl]], [[Resolution|resolution]] 1.91Å' scene=''> | ||
== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>[[4yyl]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4YYL OCA]. For a <b>guided tour on the structure components</b> use [ | <table><tr><td colspan='2'>[[4yyl]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Influenza_A_virus_(A/Puerto_Rico/8/1934(H1N1)) Influenza A virus (A/Puerto Rico/8/1934(H1N1))]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4YYL OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4YYL FirstGlance]. <br> | ||
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=4KN:2-(4-FLUOROPHENOXY)-1-(2,3,4-TRIHYDROXYPHENYL)ETHANONE'>4KN</scene>, <scene name='pdbligand=MN:MANGANESE+(II)+ION'>MN</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></td></tr> | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.905Å</td></tr> | ||
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[ | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=4KN:2-(4-FLUOROPHENOXY)-1-(2,3,4-TRIHYDROXYPHENYL)ETHANONE'>4KN</scene>, <scene name='pdbligand=MN:MANGANESE+(II)+ION'>MN</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</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=4yyl FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4yyl OCA], [https://pdbe.org/4yyl PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4yyl RCSB], [https://www.ebi.ac.uk/pdbsum/4yyl PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4yyl ProSAT]</span></td></tr> | |||
</table> | </table> | ||
== Function == | == Function == | ||
[ | [https://www.uniprot.org/uniprot/PA_I34A1 PA_I34A1] Implicated in endonuclease cleavage of capped RNA primers. Displays an elongation factor activity in viral RNA synthesis. Dispensable for viral transcription, but not replication. | ||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
Seasonal epidemics and occasional pandemics caused by influenza viruses are global threats to humans. Since the efficacy of currently approved drugs is limited by the emerging resistance of the viruses, the development of new antiviral drugs is still demanded. Endonuclease activity, which lies in the influenza polymerase acidic protein N-terminal domain (PAN), is a potent target for novel antiviral agents. Here, we report the identification of some novel inhibitors for PAN endonuclease activity. The binding mode of one of the inhibitory compounds to PAN was investigated in detail by means of X-ray crystal structure analysis and molecular dynamics (MD) simulation. It was observed in the crystal structure that three molecules of the same kind of inhibitor were bound to one PAN. One of the three molecules is located at the active site and makes a chelation to metal ions. Another molecule is positioned at the space adjacent to the metal-chelated site. The other molecule is located at a site slightly apart from the metal-chelated site, causing a conformational change of Arg124. The last binding site was not observed in previous crystallographic studies. Hence, the stability of inhibitor binding was examined by performing 100-ns MD simulation. During the MD simulation, the three inhibitor molecules fluctuated at the respective binding sites at different amplitudes, while all of the molecules maintained interactions with the protein. Molecular mechanics/generalized Born surface area (MM/GBSA) analysis suggested that the molecule in the last binding site has a higher affinity than the others. Structural information obtained in this study will provide a hint for designing and developing novel potent agents against influenza viruses. | |||
Structural and computational study on inhibitory compounds for endonuclease activity of influenza virus polymerase.,Fudo S, Yamamoto N, Nukaga M, Odagiri T, Tashiro M, Neya S, Hoshino T Bioorg Med Chem. 2015 Sep 1;23(17):5466-75. doi: 10.1016/j.bmc.2015.07.046. Epub , 2015 Jul 29. PMID:26252962<ref>PMID:26252962</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
<div class="pdbe-citations 4yyl" style="background-color:#fffaf0;"></div> | |||
==See Also== | |||
*[[RNA polymerase 3D structures|RNA polymerase 3D structures]] | |||
== References == | |||
<references/> | |||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
[[Category: Fudo | [[Category: Large Structures]] | ||
[[Category: Hoshino | [[Category: Fudo S]] | ||
[[Category: Neya | [[Category: Hoshino T]] | ||
[[Category: Nukaga | [[Category: Neya S]] | ||
[[Category: Odagiri | [[Category: Nukaga M]] | ||
[[Category: Tashiro | [[Category: Odagiri T]] | ||
[[Category: Yamamoto | [[Category: Tashiro M]] | ||
[[Category: Yamamoto N]] | |||
Latest revision as of 18:40, 8 November 2023
Phenolic acid derivative bound to influenza strain H1N1 polymerase subunit PA endonucleasePhenolic acid derivative bound to influenza strain H1N1 polymerase subunit PA endonuclease
Structural highlights
FunctionPA_I34A1 Implicated in endonuclease cleavage of capped RNA primers. Displays an elongation factor activity in viral RNA synthesis. Dispensable for viral transcription, but not replication. Publication Abstract from PubMedSeasonal epidemics and occasional pandemics caused by influenza viruses are global threats to humans. Since the efficacy of currently approved drugs is limited by the emerging resistance of the viruses, the development of new antiviral drugs is still demanded. Endonuclease activity, which lies in the influenza polymerase acidic protein N-terminal domain (PAN), is a potent target for novel antiviral agents. Here, we report the identification of some novel inhibitors for PAN endonuclease activity. The binding mode of one of the inhibitory compounds to PAN was investigated in detail by means of X-ray crystal structure analysis and molecular dynamics (MD) simulation. It was observed in the crystal structure that three molecules of the same kind of inhibitor were bound to one PAN. One of the three molecules is located at the active site and makes a chelation to metal ions. Another molecule is positioned at the space adjacent to the metal-chelated site. The other molecule is located at a site slightly apart from the metal-chelated site, causing a conformational change of Arg124. The last binding site was not observed in previous crystallographic studies. Hence, the stability of inhibitor binding was examined by performing 100-ns MD simulation. During the MD simulation, the three inhibitor molecules fluctuated at the respective binding sites at different amplitudes, while all of the molecules maintained interactions with the protein. Molecular mechanics/generalized Born surface area (MM/GBSA) analysis suggested that the molecule in the last binding site has a higher affinity than the others. Structural information obtained in this study will provide a hint for designing and developing novel potent agents against influenza viruses. Structural and computational study on inhibitory compounds for endonuclease activity of influenza virus polymerase.,Fudo S, Yamamoto N, Nukaga M, Odagiri T, Tashiro M, Neya S, Hoshino T Bioorg Med Chem. 2015 Sep 1;23(17):5466-75. doi: 10.1016/j.bmc.2015.07.046. Epub , 2015 Jul 29. PMID:26252962[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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