7ul1 | pdb_00007ul1
Crystal structure of SARS-CoV-2 RBD in complex with the neutralizing IGHV3-53-encoded antibody EH3 isolated from a nonvaccinated pediatric patient
Structural highlights
FunctionSPIKE_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][1] [2] [3] 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 PubMedNeutralizing antibodies (NAbs) hold great promise for clinical interventions against SARS-CoV-2 variants of concern (VOCs). Understanding NAb epitope-dependent antiviral mechanisms is crucial for developing vaccines and therapeutics against VOCs. Here we characterized two potent NAbs, EH3 and EH8, isolated from an unvaccinated pediatric patient with exceptional plasma neutralization activity. EH3 and EH8 cross-neutralize the early VOCs and mediate strong Fc-dependent effector activity in vitro. Structural analyses of EH3 and EH8 in complex with the receptor-binding domain (RBD) revealed the molecular determinants of the epitope-driven protection and VOC evasion. While EH3 represents the prevalent IGHV3-53 NAb whose epitope substantially overlaps with the ACE2 binding site, EH8 recognizes a narrow epitope exposed in both RBD-up and RBD-down conformations. When tested in vivo, a single-dose prophylactic administration of EH3 fully protected stringent K18-hACE2 mice from lethal challenge with Delta VOC. Our study demonstrates that protective NAbs responses converge in pediatric and adult SARS-CoV-2 patients. Molecular basis for antiviral activity of two pediatric neutralizing antibodies targeting SARS-CoV-2 Spike RBD.,Chen Y, Prevost J, Ullah I, Romero H, Lisi V, Tolbert WD, Grover JR, Ding S, Gong SY, Beaudoin-Bussieres G, Gasser R, Benlarbi M, Vezina D, Anand SP, Chatterjee D, Goyette G, Grunst MW, Yang Z, Bo Y, Zhou F, Beland K, Bai X, Zeher AR, Huang RK, Nguyen DN, Sherburn R, Wu D, Piszczek G, Pare B, Matthies D, Xia D, Richard J, Kumar P, Mothes W, Cote M, Uchil PD, Lavallee VP, Smith MA, Pazgier M, Haddad E, Finzi A iScience. 2023 Jan 20;26(1):105783. doi: 10.1016/j.isci.2022.105783. Epub 2022 , Dec 9. PMID:36514310[4] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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