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| | ==Complex of H275Y/I223V mutant variant of neuraminidase from H1N1 influenza virus with oseltamivir== | | ==Complex of H275Y/I223V mutant variant of neuraminidase from H1N1 influenza virus with oseltamivir== |
| - | <StructureSection load='5nzf' size='340' side='right' caption='[[5nzf]], [[Resolution|resolution]] 1.75Å' scene=''> | + | <StructureSection load='5nzf' size='340' side='right'caption='[[5nzf]], [[Resolution|resolution]] 1.75Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[5nzf]] is a 4 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5NZF OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5NZF FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[5nzf]] is a 4 chain structure with sequence from [http://en.wikipedia.org/wiki/Influenza_virus Influenza virus]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5NZF OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=5NZF FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=BMA:BETA-D-MANNOSE'>BMA</scene>, <scene name='pdbligand=CA:CALCIUM+ION'>CA</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=G39:(3R,4R,5S)-4-(ACETYLAMINO)-5-AMINO-3-(PENTAN-3-YLOXY)CYCLOHEX-1-ENE-1-CARBOXYLIC+ACID'>G39</scene>, <scene name='pdbligand=MAN:ALPHA-D-MANNOSE'>MAN</scene>, <scene name='pdbligand=NA:SODIUM+ION'>NA</scene>, <scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</scene></td></tr> | + | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=BMA:BETA-D-MANNOSE'>BMA</scene>, <scene name='pdbligand=CA:CALCIUM+ION'>CA</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=G39:(3R,4R,5S)-4-(ACETYLAMINO)-5-AMINO-3-(PENTAN-3-YLOXY)CYCLOHEX-1-ENE-1-CARBOXYLIC+ACID'>G39</scene>, <scene name='pdbligand=NA:SODIUM+ION'>NA</scene>, <scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</scene>, <scene name='pdbligand=MAN:ALPHA-D-MANNOSE'>MAN</scene></td></tr> |
| | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[5nwe|5nwe]], [[5nz4|5nz4]], [[5nze|5nze]], [[5nzn|5nzn]]</td></tr> | | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[5nwe|5nwe]], [[5nz4|5nz4]], [[5nze|5nze]], [[5nzn|5nzn]]</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=5nzf FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5nzf OCA], [http://pdbe.org/5nzf PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5nzf RCSB], [http://www.ebi.ac.uk/pdbsum/5nzf PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5nzf ProSAT]</span></td></tr> | + | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">NA ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=11309 Influenza virus])</td></tr> |
| | + | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://proteopedia.org/fgij/fg.htm?mol=5nzf FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5nzf OCA], [http://pdbe.org/5nzf PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5nzf RCSB], [http://www.ebi.ac.uk/pdbsum/5nzf PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5nzf ProSAT]</span></td></tr> |
| | </table> | | </table> |
| | == Function == | | == Function == |
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| | </div> | | </div> |
| | <div class="pdbe-citations 5nzf" style="background-color:#fffaf0;"></div> | | <div class="pdbe-citations 5nzf" style="background-color:#fffaf0;"></div> |
| | + | |
| | + | ==See Also== |
| | + | *[[Neuraminidase 3D structures|Neuraminidase 3D structures]] |
| | == References == | | == References == |
| | <references/> | | <references/> |
| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| | + | [[Category: Influenza virus]] |
| | + | [[Category: Large Structures]] |
| | [[Category: Pachl, P]] | | [[Category: Pachl, P]] |
| | [[Category: Pokorna, J]] | | [[Category: Pokorna, J]] |
| Structural highlights
5nzf is a 4 chain structure with sequence from Influenza virus. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
| | Ligands: | , , , , , , |
| Related: | 5nwe, 5nz4, 5nze, 5nzn |
| Gene: | NA (Influenza virus) |
| Resources: | FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT |
Function
[W5R8B8_9INFA] Catalyzes the removal of terminal sialic acid residues from viral and cellular glycoconjugates. Cleaves off the terminal sialic acids on the glycosylated HA during virus budding to facilitate virus release. Additionally helps virus spread through the circulation by further removing sialic acids from the cell surface. These cleavages prevent self-aggregation and ensure the efficient spread of the progeny virus from cell to cell. Otherwise, infection would be limited to one round of replication. Described as a receptor-destroying enzyme because it cleaves a terminal sialic acid from the cellular receptors. May facilitate viral invasion of the upper airways by cleaving the sialic acid moities on the mucin of the airway epithelial cells. Likely to plays a role in the budding process through its association with lipid rafts during intracellular transport. May additionally display a raft-association independent effect on budding. Plays a role in the determination of host range restriction on replication and virulence. Sialidase activity in late endosome/lysosome traffic seems to enhance virus replication.[HAMAP-Rule:MF_04071]
Publication Abstract from PubMed
Neuraminidase is the main target for current influenza drugs. Reduced susceptibility to oseltamivir, the most widely prescribed neuraminidase inhibitor, has been repeatedly reported. The resistance substitutions I223V and S247N, alone or in combination with the major oseltamivir-resistance mutation H275Y, have been observed in 2009 pandemic H1N1 viruses. We overexpressed and purified the ectodomain of wild-type neuraminidase from the A/California/07/2009 (H1N1) influenza virus, as well as variants containing H275Y, I223V, and S247N single mutations and H275Y/I223V and H275Y/S247N double mutations. We performed enzymological and thermodynamic analyses and structurally examined the resistance mechanism. Our results reveal that the I223V or S247N substitution alone confers only a moderate reduction in oseltamivir affinity. In contrast, the major oseltamivir resistance mutation H275Y causes a significant decrease in the enzyme’s ability to bind this drug. Combination of H275Y with an I223V or S247N mutation results in extreme impairment of oseltamivir’s inhibition potency. Our structural analyses revealed that the H275Y substitution has a major effect on the oseltamivir binding pose within the active site while the influence of other studied mutations is much less prominent. Our crystal structures also helped explain the augmenting effect on resistance of combining H275Y with both substitutions.
Kinetic, Thermodynamic, and Structural Analysis of Drug Resistance Mutations in Neuraminidase from the 2009 Pandemic Influenza Virus.,Pokorna J, Pachl P, Karlukova E, Hejdanek J, Rezacova P, Machara A, Hudlicky J, Konvalinka J, Kozisek M Viruses. 2018 Jun 21;10(7). pii: v10070339. doi: 10.3390/v10070339. PMID:29933553[1]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Pokorna J, Pachl P, Karlukova E, Hejdanek J, Rezacova P, Machara A, Hudlicky J, Konvalinka J, Kozisek M. Kinetic, Thermodynamic, and Structural Analysis of Drug Resistance Mutations in Neuraminidase from the 2009 Pandemic Influenza Virus. Viruses. 2018 Jun 21;10(7). pii: v10070339. doi: 10.3390/v10070339. PMID:29933553 doi:http://dx.doi.org/10.3390/v10070339
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