8zc3: Difference between revisions

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<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=8zc3 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=8zc3 OCA], [https://pdbe.org/8zc3 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=8zc3 RCSB], [https://www.ebi.ac.uk/pdbsum/8zc3 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=8zc3 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=8zc3 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=8zc3 OCA], [https://pdbe.org/8zc3 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=8zc3 RCSB], [https://www.ebi.ac.uk/pdbsum/8zc3 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=8zc3 ProSAT]</span></td></tr>
</table>
</table>
== Function ==
<div style="background-color:#fffaf0;">
[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]
== Publication Abstract from PubMed ==
The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike (S) protein continues to evolve antigenically, impacting antibody immunity. D1F6, an affinity-matured non-stereotypic VH1-2 antibody isolated from a patient infected with the SARS-CoV-2 ancestral strain, effectively neutralizes most Omicron variants tested, including XBB.1.5. We identify that D1F6 in the immunoglobulin G (IgG) form is able to overcome the effect of most Omicron mutations through its avidity-enhanced multivalent S-trimer binding. Cryo-electron microscopy (cryo-EM) and biochemical analyses show that three simultaneous epitope mutations are generally needed to substantially disrupt the multivalent S-trimer binding by D1F6 IgG. Antigenic mutations at spike positions 346, 444, and 445, which appeared in the latest variants, have little effect on D1F6 binding individually. However, these mutations are able to act synergistically with earlier Omicron mutations to impair neutralization by affecting the interaction between D1F6 IgG and the S-trimer. These results provide insight into the mechanism by which accumulated antigenic mutations facilitate evasion of affinity-matured antibodies.
 
An unconventional VH1-2 antibody tolerates escape mutations and shows an antigenic hotspot on SARS-CoV-2 spike.,Liu B, Niu X, Deng Y, Zhang Z, Wang Y, Gao X, Liang H, Li Z, Wang Q, Cheng Y, Chen Q, Huang S, Pan Y, Su M, Lin X, Niu C, Chen Y, Yang W, Zhang Y, Yan Q, He J, Zhao J, Chen L, Xiong X Cell Rep. 2024 May 27;43(6):114265. doi: 10.1016/j.celrep.2024.114265. PMID:38805396<ref>PMID:38805396</ref>
 
From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 8zc3" style="background-color:#fffaf0;"></div>
== References ==
== References ==
<references/>
<references/>

Latest revision as of 08:28, 12 June 2024

SARS-CoV-2 Omicron BA.4 spike trimer (6P) in complex with 3 D1F6 Fabs (1 RBD up)SARS-CoV-2 Omicron BA.4 spike trimer (6P) in complex with 3 D1F6 Fabs (1 RBD up)

Structural highlights

8zc3 is a 9 chain structure with sequence from Homo sapiens and Severe acute respiratory syndrome coronavirus 2. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:Electron Microscopy, Resolution 4.69Å
Ligands:
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Publication Abstract from PubMed

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike (S) protein continues to evolve antigenically, impacting antibody immunity. D1F6, an affinity-matured non-stereotypic VH1-2 antibody isolated from a patient infected with the SARS-CoV-2 ancestral strain, effectively neutralizes most Omicron variants tested, including XBB.1.5. We identify that D1F6 in the immunoglobulin G (IgG) form is able to overcome the effect of most Omicron mutations through its avidity-enhanced multivalent S-trimer binding. Cryo-electron microscopy (cryo-EM) and biochemical analyses show that three simultaneous epitope mutations are generally needed to substantially disrupt the multivalent S-trimer binding by D1F6 IgG. Antigenic mutations at spike positions 346, 444, and 445, which appeared in the latest variants, have little effect on D1F6 binding individually. However, these mutations are able to act synergistically with earlier Omicron mutations to impair neutralization by affecting the interaction between D1F6 IgG and the S-trimer. These results provide insight into the mechanism by which accumulated antigenic mutations facilitate evasion of affinity-matured antibodies.

An unconventional VH1-2 antibody tolerates escape mutations and shows an antigenic hotspot on SARS-CoV-2 spike.,Liu B, Niu X, Deng Y, Zhang Z, Wang Y, Gao X, Liang H, Li Z, Wang Q, Cheng Y, Chen Q, Huang S, Pan Y, Su M, Lin X, Niu C, Chen Y, Yang W, Zhang Y, Yan Q, He J, Zhao J, Chen L, Xiong X Cell Rep. 2024 May 27;43(6):114265. doi: 10.1016/j.celrep.2024.114265. PMID:38805396[1]

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

References

  1. ↑ Liu B, Niu X, Deng Y, Zhang Z, Wang Y, Gao X, Liang H, Li Z, Wang Q, Cheng Y, Chen Q, Huang S, Pan Y, Su M, Lin X, Niu C, Chen Y, Yang W, Zhang Y, Yan Q, He J, Zhao J, Chen L, Xiong X. An unconventional VH1-2 antibody tolerates escape mutations and shows an antigenic hotspot on SARS-CoV-2 spike. Cell Rep. 2024 May 27;43(6):114265. PMID:38805396 doi:10.1016/j.celrep.2024.114265

8zc3, resolution 4.69Å

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