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| | <StructureSection load='3cl2' size='340' side='right'caption='[[3cl2]], [[Resolution|resolution]] 2.54Å' scene=''> | | <StructureSection load='3cl2' size='340' side='right'caption='[[3cl2]], [[Resolution|resolution]] 2.54Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[3cl2]] is a 8 chain structure with sequence from [https://en.wikipedia.org/wiki/Influenza_a_virus_(a/viet_nam/1203/2004(h5n1)) Influenza a virus (a/viet nam/1203/2004(h5n1))]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3CL2 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3CL2 FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[3cl2]] is a 8 chain structure with sequence from [https://en.wikipedia.org/wiki/Influenza_A_virus_(A/Viet_Nam/1203/2004(H5N1)) Influenza A virus (A/Viet Nam/1203/2004(H5N1))]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3CL2 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3CL2 FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=G39:(3R,4R,5S)-4-(ACETYLAMINO)-5-AMINO-3-(PENTAN-3-YLOXY)CYCLOHEX-1-ENE-1-CARBOXYLIC+ACID'>G39</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]] 2.538Å</td></tr> |
| - | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat"><div style='overflow: auto; max-height: 3em;'>[[3ckz|3ckz]], [[3cl0|3cl0]]</div></td></tr>
| + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=G39:(3R,4R,5S)-4-(ACETYLAMINO)-5-AMINO-3-(PENTAN-3-YLOXY)CYCLOHEX-1-ENE-1-CARBOXYLIC+ACID'>G39</scene></td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">NA ([https://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=284218 Influenza A virus (A/Viet Nam/1203/2004(H5N1))])</td></tr> | + | |
| - | <tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[https://en.wikipedia.org/wiki/Exo-alpha-sialidase Exo-alpha-sialidase], with EC number [https://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.2.1.18 3.2.1.18] </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=3cl2 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3cl2 OCA], [https://pdbe.org/3cl2 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3cl2 RCSB], [https://www.ebi.ac.uk/pdbsum/3cl2 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3cl2 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=3cl2 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3cl2 OCA], [https://pdbe.org/3cl2 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3cl2 RCSB], [https://www.ebi.ac.uk/pdbsum/3cl2 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3cl2 ProSAT]</span></td></tr> |
| | </table> | | </table> |
| | == Function == | | == Function == |
| - | [[https://www.uniprot.org/uniprot/Q6DPL2_9INFA Q6DPL2_9INFA]] Catalyzes the removal of terminal sialic acid residues from viral and cellular glycoconjugates.[RuleBase:RU361252]
| + | [https://www.uniprot.org/uniprot/NRAM_I04A1 NRAM_I04A1] 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] |
| | <div style="background-color:#fffaf0;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
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| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Exo-alpha-sialidase]] | |
| | [[Category: Large Structures]] | | [[Category: Large Structures]] |
| - | [[Category: Collins, P]] | + | [[Category: Collins P]] |
| - | [[Category: Gamblin, S J]] | + | [[Category: Gamblin SJ]] |
| - | [[Category: Haire, L F]] | + | [[Category: Haire LF]] |
| - | [[Category: Hay, A J]] | + | [[Category: Hay AJ]] |
| - | [[Category: Lin, Y P]] | + | [[Category: Lin YP]] |
| - | [[Category: Liu, J]] | + | [[Category: Liu J]] |
| - | [[Category: Martin, S R]] | + | [[Category: Martin SR]] |
| - | [[Category: Russell, R J]] | + | [[Category: Russell RJ]] |
| - | [[Category: Skehel, J J]] | + | [[Category: Skehel JJ]] |
| - | [[Category: Walker, P A]] | + | [[Category: Walker PA]] |
| - | [[Category: Glycosidase]]
| + | |
| - | [[Category: Hydrolase]]
| + | |
| - | [[Category: Membrane]]
| + | |
| - | [[Category: N1]]
| + | |
| - | [[Category: N294]]
| + | |
| - | [[Category: Neuraminidase]]
| + | |
| - | [[Category: Oseltamivir]]
| + | |
| - | [[Category: Transmembrane]]
| + | |
| - | [[Category: Viral protein]]
| + | |
| - | [[Category: Virion]]
| + | |
| Structural highlights
Function
NRAM_I04A1 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
The potential impact of pandemic influenza makes effective measures to limit the spread and morbidity of virus infection a public health priority. Antiviral drugs are seen as essential requirements for control of initial influenza outbreaks caused by a new virus, and in pre-pandemic plans there is a heavy reliance on drug stockpiles. The principal target for these drugs is a virus surface glycoprotein, neuraminidase, which facilitates the release of nascent virus and thus the spread of infection. Oseltamivir (Tamiflu) and zanamivir (Relenza) are two currently used neuraminidase inhibitors that were developed using knowledge of the enzyme structure. It has been proposed that the closer such inhibitors resemble the natural substrate, the less likely they are to select drug-resistant mutant viruses that retain viability. However, there have been reports of drug-resistant mutant selection in vitro and from infected humans. We report here the enzymatic properties and crystal structures of neuraminidase mutants from H5N1-infected patients that explain the molecular basis of resistance. Our results show that these mutants are resistant to oseltamivir but still strongly inhibited by zanamivir owing to an altered hydrophobic pocket in the active site of the enzyme required for oseltamivir binding. Together with recent reports of the viability and pathogenesis of H5N1 (ref. 7) and H1N1 (ref. 8) viruses with neuraminidases carrying these mutations, our results indicate that it would be prudent for pandemic stockpiles of oseltamivir to be augmented by additional antiviral drugs, including zanamivir.
Crystal structures of oseltamivir-resistant influenza virus neuraminidase mutants.,Collins PJ, Haire LF, Lin YP, Liu J, Russell RJ, Walker PA, Skehel JJ, Martin SR, Hay AJ, Gamblin SJ Nature. 2008 Jun 26;453(7199):1258-61. Epub 2008 May 14. PMID:18480754[1]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Collins PJ, Haire LF, Lin YP, Liu J, Russell RJ, Walker PA, Skehel JJ, Martin SR, Hay AJ, Gamblin SJ. Crystal structures of oseltamivir-resistant influenza virus neuraminidase mutants. Nature. 2008 Jun 26;453(7199):1258-61. Epub 2008 May 14. PMID:18480754 doi:http://dx.doi.org/10.1038/nature06956
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