View source for 7xdl


==Cryo-EM structure of SARS-CoV-2 Delta Spike protein in complex with BA7208 and BA7125 fab==
<StructureSection load='7xdl' size='340' side='right'caption='[[7xdl]], [[Resolution|resolution]] 3.08&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[7xdl]] is a 15 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] and [https://en.wikipedia.org/wiki/Severe_acute_respiratory_syndrome_coronavirus_2 Severe acute respiratory syndrome coronavirus 2]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7XDL OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7XDL FirstGlance]. <br>
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">Electron Microscopy, [[Resolution|Resolution]] 3.08&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><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=7xdl FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7xdl OCA], [https://pdbe.org/7xdl PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7xdl RCSB], [https://www.ebi.ac.uk/pdbsum/7xdl PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7xdl ProSAT]</span></td></tr>
</table>
== Function ==
[https://www.uniprot.org/uniprot/SPIKE_SARS2 SPIKE_SARS2] attaches the virion to the cell membrane by interacting with host receptor, initiating the infection (By similarity). Binding to human ACE2 receptor and internalization of the virus into the endosomes of the host cell induces conformational changes in the Spike glycoprotein (PubMed:32142651, PubMed:32075877, PubMed:32155444). Uses also human TMPRSS2 for priming in human lung cells which is an essential step for viral entry (PubMed:32142651). Proteolysis by cathepsin CTSL may unmask the fusion peptide of S2 and activate membranes fusion within endosomes.[HAMAP-Rule:MF_04099]<ref>PMID:32075877</ref> <ref>PMID:32142651</ref> <ref>PMID:32155444</ref>   mediates fusion of the virion and cellular membranes by acting as a class I viral fusion protein. Under the current model, the protein has at least three conformational states: pre-fusion native state, pre-hairpin intermediate state, and post-fusion hairpin state. During viral and target cell membrane fusion, the coiled coil regions (heptad repeats) assume a trimer-of-hairpins structure, positioning the fusion peptide in close proximity to the C-terminal region of the ectodomain. The formation of this structure appears to drive apposition and subsequent fusion of viral and target cell membranes.[HAMAP-Rule:MF_04099]  Acts as a viral fusion peptide which is unmasked following S2 cleavage occurring upon virus endocytosis.[HAMAP-Rule:MF_04099]
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== Publication Abstract from PubMed ==
SARS-CoV-2 Omicron subvariants have demonstrated extensive evasion from monoclonal antibodies (mAbs) developed for clinical use, which raises an urgent need to develop new broad-spectrum mAbs. Here, we report the isolation and analysis of two anti-RBD neutralizing antibodies BA7208 and BA7125 from mice engineered to produce human antibodies. While BA7125 showed broadly neutralizing activity against all variants except the Omicron sublineages, BA7208 was potently neutralizing against all tested SARS-CoV-2 variants (including Omicron BA.1-BA.5) except Mu. By combining BA7208 and BA7125 through the knobs-into-holes technology, we generated a biparatopic antibody BA7208/7125 that was able to neutralize all tested circulating SARS-CoV-2 variants. Cryo-electron microscopy structure of these broad-spectrum antibodies in complex with trimeric Delta and Omicron spike indicated that the contact residues are highly conserved and had minimal interactions with mutational residues in RBD of current variants. In addition, we showed that administration of BA7208/7125 via the intraperitoneal, intranasal, or aerosol inhalation route showed potent therapeutic efficacy against Omicron BA.1 and BA.2 in hACE2-transgenic and wild-type mice and, separately, effective prophylaxis. BA7208/7125 thus has the potential to be an effective candidate as an intervention against COVID-19.

Biparatopic antibody BA7208/7125 effectively neutralizes SARS-CoV-2 variants including Omicron BA.1-BA.5.,Wang Y, Yan A, Song D, Dong C, Rao M, Gao Y, Qi R, Ma X, Wang Q, Xu H, Liu H, Han J, Duan M, Liu S, Yu X, Zong M, Feng J, Jiao J, Zhang H, Li M, Yu B, Wang Y, Meng F, Ni X, Li Y, Shen Z, Sun B, Shao X, Zhao H, Zhao Y, Li R, Zhang Y, Du G, Lu J, You C, Jiang H, Zhang L, Wang L, Dou C, Liu Z, Zhao J Cell Discov. 2023 Jan 7;9(1):3. doi: 10.1038/s41421-022-00509-9. PMID:36609558<ref>PMID:36609558</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 7xdl" style="background-color:#fffaf0;"></div>

==See Also==
*[[Spike protein 3D structures|Spike protein 3D structures]]
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Severe acute respiratory syndrome coronavirus 2]]
[[Category: Liu S]]
[[Category: Liu Z]]
[[Category: Yuanzhu G]]