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==Alpha SARS-CoV-2 spike protein in complex with REGN10987 Fab homologue.==
<StructureSection load='9lyo' size='340' side='right'caption='[[9lyo]], [[Resolution|resolution]] 3.07&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[9lyo]] is a 9 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=9LYO OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=9LYO 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]] 3.07&#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=9lyo FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=9lyo OCA], [https://pdbe.org/9lyo PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=9lyo RCSB], [https://www.ebi.ac.uk/pdbsum/9lyo PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=9lyo 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 ==
One of the approaches for treatment of COVID-19 is a use of neutralizing antibodies (nAbs). The study of the mechanisms by which nAbs recognize different strains of SARS-CoV-2 may facilitate the development of new drugs and vaccines against the coronavirus infection. In this work, we present the 3.1 A resolution cryo-electron microscopy structure of a full-length trimeric spike-protein (S-protein) of the SARS-CoV-2 Alpha (B.1.1.7) variant in complex with the Fab of the REGN10987 nAb. In the complex, two receptor-binding domains (RBDs) of the S-protein were observed in the 'up' state, whereas third RBD was in the 'down' state. This distinguishes the obtained structure from the complex of Delta (B.1.617.2) S-protein with REGN10987-Fab, where only one RBD was in the 'up' state. Probably some of the substituted residues (K478T, A570D, and S982A) located at the interprotomer interfaces are responsible for the greater Alpha S-protein opening upon the REGN10987-Fab binding. The Fab identically binds to the RBD in the both 'up' and 'down' conformations. The RBD-Fab interaction interface was refined to a resolution of 3.6 A. The antibody binds to the receptor-binding motif (RBM), which prevents the S-protein from the binding to its receptor, angiotensin-converting enzyme 2 (ACE-2). Comparison with the structures of the Wuhan (wild type) and Delta RBD variants in complex with REGN10987-Fab revealed that the N501Y and T478K/L452R mutations presented in the RBM of the Alpha and Delta variants, respectively, do not affect the mode of the RBD-Fab interaction.

Structure and dynamics of Alpha B.1.1.7 SARS-CoV-2 S-protein in complex with Fab of neutralizing antibody REGN10987.,Kocharovskaya MV, Pichkur EB, Ivannikov AD, Kharlampieva DD, Grafskaia EN, Lyukmanova EN, Kirpichnikov MP, Shenkarev ZO Biochem Biophys Res Commun. 2025 Apr 1;755:151558. doi: , 10.1016/j.bbrc.2025.151558. Epub 2025 Feb 27. PMID:40043614<ref>PMID:40043614</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 9lyo" style="background-color:#fffaf0;"></div>
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Severe acute respiratory syndrome coronavirus 2]]
[[Category: Kocharovskaya MV]]
[[Category: Lyukmanova EN]]
[[Category: Pichkur EB]]
[[Category: Shenkarev ZO]]