9j66
From Proteopedia
Cryo-EM structure of the SARS-CoV-2 S 6P trimer in complex with the human neutralizing antibody Fab fragment CAV-C65 (local refinement)
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 PubMedIgA antibodies are critical components of the mucosal immune barrier, providing essential first-line defense against viral infections. In this study, we investigated the impact of antibody class switching on neutralization efficacy by engineering recombinant antibodies of different isotypes (IgA1, IgG1) with identical variable regions from SARS-CoV-2 convalescent patients. A potent, broad-spectrum neutralizing monoclonal antibody CAV-C65 exhibited a ten-fold increase in neutralization potency upon switching from IgG1 to IgA1 monomer. Structural analysis revealed that this antibody binds to two adjacent receptor binding domains on the spike protein. Enhanced neutralization by IgA1 was attributed to the combined effects of increased affinity, unique hinge region properties, and potential cross-linking of viral particles. Inhaled CAV-C65 IgA1 demonstrated prophylactic efficacy against lethal SARS-CoV-2 infection in hACE2 mice. These findings highlight the pivotal role of IgA in antiviral immunity and inform the development of IgA-based therapeutics. IgA class switching enhances neutralizing potency against SARS-CoV-2 by increased antibody hinge flexibility.,Xu M, Zhang Z, Sun Y, Mai H, Liu S, Liu S, Lv K, Yu F, Wang Y, Yue X, Zhang J, Cai X, Zhao R, Lu H, Liu L, Luo H, Zhao H, Wang Y, Gong P, Chen S, Jing X, Zhao J, Chen YQ Antiviral Res. 2025 Mar;235:106082. doi: 10.1016/j.antiviral.2025.106082. Epub , 2025 Jan 17. PMID:39828085[4] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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