8vyf
SARS-CoV-2 S NTD (C.37 Lambda variant) plus S2L20 and S2X303 Fabs, 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 PubMedIn the ENSEMBLE randomized, placebo-controlled phase 3 trial (NCT04505722), estimated single-dose Ad26.COV2.S vaccine efficacy (VE) was 56% against moderate to severe-critical COVID-19. SARS-CoV-2 Spike sequences were determined from 484 vaccine and 1,067 placebo recipients who acquired COVID-19. In this set of prespecified analyses, we show that in Latin America, VE was significantly lower against Lambda vs. Reference and against Lambda vs. non-Lambda [family-wise error rate (FWER) p < 0.05]. VE differed by residue match vs. mismatch to the vaccine-insert at 16 amino acid positions (4 FWER p < 0.05; 12 q-value </= 0.20); significantly decreased with physicochemical-weighted Hamming distance to the vaccine-strain sequence for Spike, receptor-binding domain, N-terminal domain, and S1 (FWER p < 0.001); differed (FWER </= 0.05) by distance to the vaccine strain measured by 9 antibody-epitope escape scores and 4 NTD neutralization-impacting features; and decreased (p = 0.011) with neutralization resistance level to vaccinee sera. VE against severe-critical COVID-19 was stable across most sequence features but lower against the most distant viruses. Quantifying how single dose Ad26.COV2.S vaccine efficacy depends on Spike sequence features.,Magaret CA, Li L, deCamp AC, Rolland M, Juraska M, Williamson BD, Ludwig J, Molitor C, Benkeser D, Luedtke A, Simpkins B, Heng F, Sun Y, Carpp LN, Bai H, Dearlove BL, Giorgi EE, Jongeneelen M, Brandenburg B, McCallum M, Bowen JE, Veesler D, Sadoff J, Gray GE, Roels S, Vandebosch A, Stieh DJ, Le Gars M, Vingerhoets J, Grinsztejn B, Goepfert PA, de Sousa LP, Silva MST, Casapia M, Losso MH, Little SJ, Gaur A, Bekker LG, Garrett N, Truyers C, Van Dromme I, Swann E, Marovich MA, Follmann D, Neuzil KM, Corey L, Greninger AL, Roychoudhury P, Hyrien O, Gilbert PB Nat Commun. 2024 Mar 11;15(1):2175. doi: 10.1038/s41467-024-46536-w. PMID:38467646[4] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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