9k6j
From Proteopedia
Crystal structure of SARS-CoV-2 WT RBD bound with P5-1C8 Fab
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 PubMedMechanistic studies of viral neutralization typically prioritize high-affinity antibodies, relegating low-affinity binders to the sidelines. P5â1C8, a Class 1 SARS-CoV-2 antibody that exemplifies this underexplored "lowâaffinity yet highâpotency" phenotype is reported, retaining strong neutralization of Omicron JN.1 despite markedly weakened trimer binding (K(D) = 225 nM; IC(50) = 0.06 nM). Structural and biophysical analyses reveal that P5-1C8 engages WT and BA.1 spikes through canonical intra-spike bivalency, but with JN.1 it induces aggregation. Using virion-like nanoparticles displaying multiple spikes, it is shown that IgG remains bound with no detectable dissociation and triggers pronounced aggregation. Coarse-grained molecular dynamics delineate the stepwise pathway in which weak IgG-spike contacts seed aggregation via transient inter-spike bridging. Together, these findings establish the first mechanistic framework demonstrating how weak-binding antibodies can nonetheless achieve potent neutralization through higher-order aggregation, thereby expanding the conceptual landscape of antibody function and opening new directions for antibody evaluation and design. IgG-Bridging-Seeded Synergistic Aggregation of SARS-CoV-2 Spikes Underlies Potent Neutralization by a Low-Affinity Antibody.,Lv N, Chen P, Dai X, Xu H, Li Z, Shan Z, Li J, Guo F, Chen Y, Li J, Huang Y, Dong G, Jiang Y, Chen L, Nan X, Zhao H, Zhang K, Fan S, Dong Y, Liu D, Wang X, Huang D, Pan X, Chen C, Liu Z, Yan LT, Zhang Q, Zhang L, Zhao Y, Yang YR Adv Sci (Weinh). 2025 Dec 7:e17192. doi: 10.1002/advs.202517192. PMID:41355083[4] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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