5w2w

From Proteopedia

(Difference between revisions)

Current revision

INFLUENZA VIRUS NEURAMINIDASE N9 IN COMPLEX WITH 8-DEOXYGENATED 2,3-DIFLUORO-N-ACETYLNEURAMINIC ACID

Structural highlights

5w2w is a 1 chain structure with sequence from Influenza A virus (A/tern/Australia/G70C/1975(H11N9)). Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 1.85Å
Ligands:	, , , , , ,
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

NRAM_I75A5 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.

Publication Abstract from PubMed

Competitive inhibitors of the influenza neuraminidase (NA) were discovered almost 20 years ago, with zanamivir and oseltamivir licensed globally. These compounds are based on a transition state analogue of the sialic acid substrate. We recently showed that 5-N-(acetylamino)-2,3,5-trideoxy-2,3-difluoro-d-erythro-beta-l-manno-2-nonulopyra nosonic acid (DFSA) and its derivatives are also potent inhibitors of the influenza NA. They are mechanism based inhibitors, forming a covalent bond between the C2 of the sugar ring and Y406 in the NA active site, thus inactivating the enzyme. We have now synthesized a series of deoxygenated DFSA derivatives in order to understand the contribution of each hydroxyl in DFSA to binding and inhibition of the influenza NA. We have investigated their relative efficacy in enzyme assays in vitro, in cell culture, and by X-ray crystallography. We found loss of the 8- and 9-OH had the biggest impact on the affinity of binding and antiviral potency.

Structural and Functional Analysis of Anti-Influenza Activity of 4-, 7-, 8- and 9-Deoxygenated 2,3-Difluoro-N-acetylneuraminic Acid Derivatives.,McKimm-Breschkin JL, Barrett S, Pilling PA, Hader S, Watts AG, Streltsov VA J Med Chem. 2018 Feb 15. doi: 10.1021/acs.jmedchem.7b01467. PMID:29397718^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ McKimm-Breschkin JL, Barrett S, Pilling PA, Hader S, Watts AG, Streltsov VA. Structural and Functional Analysis of Anti-Influenza Activity of 4-, 7-, 8- and 9-Deoxygenated 2,3-Difluoro-N-acetylneuraminic Acid Derivatives. J Med Chem. 2018 Feb 15. doi: 10.1021/acs.jmedchem.7b01467. PMID:29397718 doi:http://dx.doi.org/10.1021/acs.jmedchem.7b01467

1 Structural highlights
2 Function
3 Publication Abstract from PubMed
4 See Also
5 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/5w2w"

@@ Line 5: / Line 5: @@
 <table><tr><td colspan='2'>[[5w2w]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Influenza_A_virus_(A/tern/Australia/G70C/1975(H11N9)) Influenza A virus (A/tern/Australia/G70C/1975(H11N9))]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5W2W OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5W2W 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]] 1.85&#8491;</td></tr>
-<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=9S7:5-acetamido-2,6-anhydro-3,5,8-trideoxy-3-fluoro-D-threo-L-galacto-nononic+acid'>9S7</scene>, <scene name='pdbligand=9SD:(2~{R},3~{R},4~{R},5~{R})-3-acetamido-2-[(1~{R})-1,3-bis(oxidanyl)propyl]-5-fluoranyl-4-oxidanyl-2,3,4,5-tetrahydropyran-1-ium-6-carboxylic+acid'>9SD</scene>, <scene name='pdbligand=9SP:(2R,3R,4R,5R,6R)-5-acetamido-6-[(1R)-1,3-bis(oxidanyl)propyl]-2,3-bis(fluoranyl)-4-oxidanyl-oxane-2-carboxylic+acid'>9SP</scene>, <scene name='pdbligand=BMA:BETA-D-MANNOSE'>BMA</scene>, <scene name='pdbligand=CA:CALCIUM+ION'>CA</scene>, <scene name='pdbligand=MAN:ALPHA-D-MANNOSE'>MAN</scene>, <scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</scene></td></tr>
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=9S7:5-(acetylamino)-2,6-anhydro-3,5,8-trideoxy-3-fluoro-D-threo-L-galacto-nononic+acid'>9S7</scene>, <scene name='pdbligand=9SD:(2R,3R,4R,5R)-3-(acetylamino)-6-carboxy-2-[(1R)-1,3-dihydroxypropyl]-5-fluoro-4-hydroxy-2,3,4,5-tetrahydropyranium+(non-preferred+name)'>9SD</scene>, <scene name='pdbligand=9SP:(2R,3R,4R,5R,6R)-5-(acetylamino)-6-[(1R)-1,3-dihydroxypropyl]-2,3-difluoro-4-hydroxytetrahydro-2H-pyran-2-carboxylic+acid+(non-preferred+name)'>9SP</scene>, <scene name='pdbligand=BMA:BETA-D-MANNOSE'>BMA</scene>, <scene name='pdbligand=CA:CALCIUM+ION'>CA</scene>, <scene name='pdbligand=MAN:ALPHA-D-MANNOSE'>MAN</scene>, <scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</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=5w2w FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5w2w OCA], [https://pdbe.org/5w2w PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5w2w RCSB], [https://www.ebi.ac.uk/pdbsum/5w2w PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5w2w ProSAT]</span></td></tr>
 </table>

5w2w

From Proteopedia

Current revision

INFLUENZA VIRUS NEURAMINIDASE N9 IN COMPLEX WITH 8-DEOXYGENATED 2,3-DIFLUORO-N-ACETYLNEURAMINIC ACID

Structural highlights

Function

Publication Abstract from PubMed

See Also

References

Contents

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