|
|
| Line 3: |
Line 3: |
| | <StructureSection load='7as3' size='340' side='right'caption='[[7as3]], [[Resolution|resolution]] 1.65Å' scene=''> | | <StructureSection load='7as3' size='340' side='right'caption='[[7as3]], [[Resolution|resolution]] 1.65Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[7as3]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Influenza_a_virus_(a/california/07/2009(h1n1)) Influenza a virus (a/california/07/2009(h1n1))]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7AS3 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7AS3 FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[7as3]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Influenza_A_virus_(A/California/07/2009(H1N1)) Influenza A virus (A/California/07/2009(H1N1))]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7AS3 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7AS3 FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><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></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]] 1.65Å</td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">PB2 ([https://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=641809 Influenza A virus (A/California/07/2009(H1N1))])</td></tr>
| + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><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></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=7as3 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7as3 OCA], [https://pdbe.org/7as3 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7as3 RCSB], [https://www.ebi.ac.uk/pdbsum/7as3 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7as3 ProSAT]</span></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=7as3 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7as3 OCA], [https://pdbe.org/7as3 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7as3 RCSB], [https://www.ebi.ac.uk/pdbsum/7as3 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7as3 ProSAT]</span></td></tr> |
| | </table> | | </table> |
| | == Function == | | == Function == |
| - | [[https://www.uniprot.org/uniprot/C3W5X5_9INFA C3W5X5_9INFA]] 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. Recognizes and binds the 7-methylguanosine-containing cap of the target pre-RNA which is subsequently cleaved after 10-13 nucleotides by the viral protein PA. Plays a role in the initiation of the viral genome replication and modulates the activity of the ribonucleoprotein (RNP) complex.[HAMAP-Rule:MF_04062]
| + | [https://www.uniprot.org/uniprot/C3W5X5_9INFA C3W5X5_9INFA] 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. Recognizes and binds the 7-methylguanosine-containing cap of the target pre-RNA which is subsequently cleaved after 10-13 nucleotides by the viral protein PA. Plays a role in the initiation of the viral genome replication and modulates the activity of the ribonucleoprotein (RNP) complex.[HAMAP-Rule:MF_04062] |
| | <div style="background-color:#fffaf0;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
| Line 19: |
Line 19: |
| | </div> | | </div> |
| | <div class="pdbe-citations 7as3" style="background-color:#fffaf0;"></div> | | <div class="pdbe-citations 7as3" style="background-color:#fffaf0;"></div> |
| | + | |
| | + | ==See Also== |
| | + | *[[RNA polymerase 3D structures|RNA polymerase 3D structures]] |
| | == References == | | == References == |
| | <references/> | | <references/> |
| Line 24: |
Line 27: |
| | </StructureSection> | | </StructureSection> |
| | [[Category: Large Structures]] | | [[Category: Large Structures]] |
| - | [[Category: Brynda, J]] | + | [[Category: Brynda J]] |
| - | [[Category: Radilova, K]] | + | [[Category: Radilova K]] |
| - | [[Category: Influenza some]]
| + | |
| - | [[Category: Polymerase]]
| + | |
| - | [[Category: Polymerase basic protein 2]]
| + | |
| - | [[Category: Viral protein]]
| + | |
| - | [[Category: Vx787]]
| + | |
| Structural highlights
Function
C3W5X5_9INFA 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. Recognizes and binds the 7-methylguanosine-containing cap of the target pre-RNA which is subsequently cleaved after 10-13 nucleotides by the viral protein PA. Plays a role in the initiation of the viral genome replication and modulates the activity of the ribonucleoprotein (RNP) complex.[HAMAP-Rule:MF_04062]
Publication Abstract from PubMed
Influenza A virus (IAV) encodes a polymerase composed of three subunits: PA, with endonuclease activity, PB1 with polymerase activity and PB2 with host RNA five-prime cap binding site. Their cooperation and stepwise activation include a process called cap-snatching, which is a crucial step in the IAV life cycle. Reproduction of IAV can be blocked by disrupting the interaction between the PB2 domain and the five-prime cap. An inhibitor of this interaction called pimodivir (VX-787) recently entered the third phase of clinical trial; however, several mutations in PB2 that cause resistance to pimodivir were observed. First major mutation, F404Y, causing resistance was identified during preclinical testing, next the mutation M431I was identified in patients during the second phase of clinical trials. The mutation H357N was identified during testing of IAV strains at Centers for Disease Control and Prevention. We set out to provide a structural and thermodynamic analysis of the interactions between cap-binding domain of PB2 wild-type and PB2 variants bearing these mutations and pimodivir. Here we present four crystal structures of PB2-WT, PB2-F404Y, PB2-M431I and PB2-H357N in complex with pimodivir. We have thermodynamically analysed all PB2 variants and proposed the effect of these mutations on thermodynamic parameters of these interactions and pimodivir resistance development. These data will contribute to understanding the effect of these missense mutations to the resistance development and help to design next generation inhibitors.
Structural and Thermodynamic Analysis of the Resistance Development to Pimodivir (VX-787), the Clinical Inhibitor of Cap Binding to PB2 Subunit of Influenza A Polymerase.,Gregor J, Radilova K, Brynda J, Fanfrlik J, Konvalinka J, Kozisek M Molecules. 2021 Feb 14;26(4). pii: molecules26041007. doi:, 10.3390/molecules26041007. PMID:33673017[1]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Gregor J, Radilova K, Brynda J, Fanfrlik J, Konvalinka J, Kozisek M. Structural and Thermodynamic Analysis of the Resistance Development to Pimodivir (VX-787), the Clinical Inhibitor of Cap Binding to PB2 Subunit of Influenza A Polymerase. Molecules. 2021 Feb 14;26(4). pii: molecules26041007. doi:, 10.3390/molecules26041007. PMID:33673017 doi:http://dx.doi.org/10.3390/molecules26041007
|
