View source for 6lxi


==Crystal structure of Z2B3 Fab in complex with influenza virus neuraminidase from A/Brevig Mission/1/1918 (H1N1)==
<StructureSection load='6lxi' size='340' side='right'caption='[[6lxi]], [[Resolution|resolution]] 2.50&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[6lxi]] is a 6 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] and [https://en.wikipedia.org/wiki/Influenza_A_virus_(A/Brevig_Mission/1/1918(H1N1)) Influenza A virus (A/Brevig Mission/1/1918(H1N1))]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6LXI OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6LXI 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]] 2.5&#8491;</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=FUC:ALPHA-L-FUCOSE'>FUC</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=6lxi FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6lxi OCA], [https://pdbe.org/6lxi PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6lxi RCSB], [https://www.ebi.ac.uk/pdbsum/6lxi PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6lxi ProSAT]</span></td></tr>
</table>
== Function ==
[https://www.uniprot.org/uniprot/NRAM_I18A0 NRAM_I18A0] 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 (By similarity).  Unlike other strains, A/WSN/33 neuraminidase binds and activates plasminogen into plasmin in the vicinity of HA so that activated plasmin cleaves HA rendering the virus infectious (By similarity).
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== Publication Abstract from PubMed ==
Here, we investigate a monoclonal antibody, Z2B3, isolated from an H7N9-infected patient, that exhibited cross-reactivity to both N9 (group 2) and a broad range of seasonal and avian N1 (group 1) proteins but lost activity to the N1 with the substitution K432E. This substitution exists in 99.25% of seasonal influenza strains after 2013. The NA-Z2B3 complex structures indicated that Z2B3 binds within the conserved active site of the neuraminidase (NA) protein. A salt bridge between D102 in Z2B3 and K432 in NA plays an important role in binding. Structure-based modification of Z2B3 with D102R in heavy chain reversed the salt bridge and restored the binding and inhibition of N1 with E432. Furthermore, Z2B3-D102R can protect mice from A/Serbia/NS-601/2014 H1N1 virus (NA contains E432) infection while the wild-type Z2B3 antibody shows no protection. This study demonstrates that a broadly reactive and protective antibody to NA can be in principle edited to restore binding and inhibition to recently drifted N1 NA and regain protection against the variant influenza strain.IMPORTANCE The immune system produces antibodies to protect the human body from harmful invaders. The monoclonal antibody (MAb) is one kind of effective antivirals. In this study, we isolated an antibody (Z2B3) from an H7N9 influenza virus-infected child. It shows cross-reactivity to both group 1 (N1) and group 2 (N9) neuraminidases (NAs) but is sensitive to N1 NA with a K432E substitution. Structural analysis of the NA-antibody fragment antigen-binding (Fab) complex provides a clue for antibody modification, and the modified antibody restored binding and inhibition to recently drifted N1 NA and regained protection against the variant influenza strain. This finding suggests that antibodies to NA may be a useful therapy and can be in principle edited to defeat drifted influenza virus.

Structure-Based Modification of an Anti-neuraminidase Human Antibody Restores Protection Efficacy against the Drifted Influenza Virus.,Jiang H, Peng W, Qi J, Chai Y, Song H, Bi Y, Rijal P, Wang H, Oladejo BO, Liu J, Shi Y, Gao GF, Townsend AR, Wu Y mBio. 2020 Oct 6;11(5):e02315-20. doi: 10.1128/mBio.02315-20. PMID:33024040<ref>PMID:33024040</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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<div class="pdbe-citations 6lxi" style="background-color:#fffaf0;"></div>

==See Also==
*[[Monoclonal Antibodies 3D structures|Monoclonal Antibodies 3D structures]]
*[[Neuraminidase 3D structures|Neuraminidase 3D structures]]
== References ==
<references/>
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</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Chai Y]]
[[Category: Gao GF]]
[[Category: Jiang H]]
[[Category: Peng W]]
[[Category: Qi J]]
[[Category: Shi Y]]
[[Category: Song H]]
[[Category: Wu Y]]