View source for 9ysg


==Cryo-EM structure of SARS-CoV-2 Omicron neutralizing antibody AB2-122 with BA.5 RBD and SP1-77 Fab complex==
<StructureSection load='9ysg' size='340' side='right'caption='[[9ysg]], [[Resolution|resolution]] 3.00&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[9ysg]] is a 5 chain structure with sequence from [https://en.wikipedia.org/wiki/Mus_musculus Mus musculus] and [https://en.wikipedia.org/wiki/Severe_acute_respiratory_syndrome_coronavirus Severe acute respiratory syndrome coronavirus]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=9YSG OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=9YSG 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&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=FUC:ALPHA-L-FUCOSE'>FUC</scene>, <scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</scene>, <scene name='pdbligand=TYS:O-SULFO-L-TYROSINE'>TYS</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=9ysg FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=9ysg OCA], [https://pdbe.org/9ysg PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=9ysg RCSB], [https://www.ebi.ac.uk/pdbsum/9ysg PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=9ysg 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 ==
During V(D)J recombination, antibody diversity is enhanced by nontemplated junctional modifications that generate immensely diverse heavy chain (HC) and light chain (LC) complementarity-determining 3 antigen-contact regions (CDR3s). We previously developed a mouse model that generates diverse antibody repertoires by rearranging a single human V(H)1-2 and Vkappa1-33, associated with highly diverse CDR3s generated by V(D)J recombination with mouse Ds and/or Js. Immunization of this model with SARS-CoV-2 D614G spike elicited an antibody that potently neutralized SARS-CoV-2 variants through Omicron BA.2.754. Here, we report a related mouse model in which a single V(H)1-2 rearranges to human D3-3 and J(H)6, generating diverse HC-CDR3s much longer on average than those of our prior model. Omicron BA.4/.5 spike-ferritin nanoparticle-immunization of the new model elicited four highly related humanized antibodies that potently neutralize downstream Omicron subvariants. All four antibodies had 12 AA HC-CDR3s with two aromatic amino acids that engage an epitope comprising a hydrophobic patch opened-up by early Omicron lineage mutations and conserved in subsequent variants. Immunization of our prior, shorter CDR3-based model, elicited slightly less potent neutralizing antibodies that bound the same Omicron epitope, and were similar in all other aspects to those from the long, fully human CDR3 model. One tested antibody from each set reduced lung viral titers in a mouse-adapted BQ1.1 challenge. The antibodies we describe are related in their epitope recognition to recently described antibodies from Omicron-infected humans. These studies validate the utility of single human V(H)- and Vkappa-rearranging mice for discovering humanized antibodies that neutralize emerging pathogens.

Recurrent SARS-CoV-2 Omicron broadly neutralizing humanized antibodies in different single human V(H)1-2-rearranging mouse models.,Batra H, Luo S, Saunders KO, Higgins JS, Jian F, Zhang J, Kibria MG, Jonaid GM, Zhou QJ, Eaton A, Cronin K, Mallory ML, Mattocks M, Edwards RJ, Parks R, Lee EM, Ye AY, Williams AC, Jung G, Mansouri K, Alam SM, Montefiori DC, Tian M, Baric RS, Cao Y, Haynes BF, Chen B, Alt FW Proc Natl Acad Sci U S A. 2026 Mar 31;123(13):e2537053123. doi: , 10.1073/pnas.2537053123. Epub 2026 Mar 23. PMID:41871249<ref>PMID:41871249</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Large Structures]]
[[Category: Mus musculus]]
[[Category: Severe acute respiratory syndrome coronavirus]]
[[Category: Alt FW]]
[[Category: Batra H]]
[[Category: Chen B]]
[[Category: Jonaid G]]
[[Category: Kibria G]]