9z3k: Difference between revisions
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==SARS-CoV-2 S2 trimer stabilized in the early fusion intermediate conformation by circular permutation and clamping by gp41 (E-FICs-v1)== | |||
<StructureSection load='9z3k' size='340' side='right'caption='[[9z3k]], [[Resolution|resolution]] 3.30Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[9z3k]] is a 3 chain structure with sequence from [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=9Z3K OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=9Z3K 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]] 3.3Å</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=9z3k FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=9z3k OCA], [https://pdbe.org/9z3k PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=9z3k RCSB], [https://www.ebi.ac.uk/pdbsum/9z3k PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=9z3k 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][https://www.uniprot.org/uniprot/SUMO_YEAST SUMO_YEAST] Ubiquitin-like protein that can be covalently attached to proteins as a monomer or a lysine-linked polymer (PubMed:9312010). Sumoylation, the attachment of SUMO to target proteins, regulates multiple cellular events (By similarity).[UniProtKB:O13351]<ref>PMID:9312010</ref> | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
The protease TMPRSS2 facilitates coronavirus infections, yet its mechanism of viral glycoprotein recognition remains unclear. Here we show that, following ACE2 engagement of the SARS-CoV-2 spike (S) inducing the early fusion intermediate conformation (E-FIC), TMPRSS2 cleaves the R815 S(2)' site and promotes fusogenic conformational changes leading to viral entry. We unveil TMPRSS2 recognition of S(2)', identify key residues modulating binding specificity and demonstrate that S(2)' site-directed broadly neutralizing antibodies target E-FIC and inhibit viral entry by blocking TMPRSS2 access. We computationally designed stabilized E-FIC as a vaccine candidate, overcoming the transient nature of this state. We describe a TMPRSS2-directed monoclonal antibody inhibiting several coronaviruses, including SARS-CoV-2 variants and protecting mice against SARS-CoV-2 challenge. These results outline the mechanistic role of TMPRSS2 and S(2)' site-directed antibodies in coronavirus entry. | |||
TMPRSS2-mediated coronavirus spike activation and inhibition.,McCallum M, Case JB, Brown JT, Park YJ, Lee J, Sutherland E, Aggarwal A, Gibson C, Lempp FA, Stewart C, Tortorici MA, Sanapala S, Low JS, Asarnow D, Bohan D, Dellota E Jr, Merz B, Chawla B, Kar S, Lanzavecchia A, Sallusto F, Riley NM, Turville S, Purcell L, Diamond MS, Veesler D Nat Struct Mol Biol. 2026 Apr 28. doi: 10.1038/s41594-026-01801-y. PMID:42050172<ref>PMID:42050172</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
[[Category: | </div> | ||
<div class="pdbe-citations 9z3k" style="background-color:#fffaf0;"></div> | |||
== References == | |||
<references/> | |||
__TOC__ | |||
</StructureSection> | |||
[[Category: Large Structures]] | |||
[[Category: Severe acute respiratory syndrome coronavirus 2]] | |||
[[Category: McCallum M]] | |||
[[Category: Veesler D]] | |||
