7e3k
From Proteopedia
Ultrapotent SARS-CoV-2 neutralizing antibodies with protective efficacy against newly emerged mutational variants
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 PubMedAccumulating mutations in the SARS-CoV-2 Spike (S) protein can increase the possibility of immune escape, challenging the present COVID-19 prophylaxis and clinical interventions. Here, 3 receptor binding domain (RBD) specific monoclonal antibodies (mAbs), 58G6, 510A5 and 13G9, with high neutralizing potency blocking authentic SARS-CoV-2 virus display remarkable efficacy against authentic B.1.351 virus. Surprisingly, structural analysis has revealed that 58G6 and 13G9 both recognize the steric region S(470-495) on the RBD, overlapping the E484K mutation presented in B.1.351. Also, 58G6 directly binds to another region S(450-458) in the RBD. Significantly, 58G6 and 510A5 both demonstrate prophylactic efficacy against authentic SARS-CoV-2 and B.1.351 viruses in the transgenic mice expressing human ACE2 (hACE2), protecting weight loss and reducing virus loads. Together, we have evidenced 2 potent neutralizing Abs with unique mechanism targeting authentic SARS-CoV-2 mutants, which can be promising candidates to fulfill the urgent needs for the prolonged COVID-19 pandemic. Potent SARS-CoV-2 neutralizing antibodies with protective efficacy against newly emerged mutational variants.,Li T, Han X, Gu C, Guo H, Zhang H, Wang Y, Hu C, Wang K, Liu F, Luo F, Zhang Y, Hu J, Wang W, Li S, Hao Y, Shen M, Huang J, Long Y, Song S, Wu R, Mu S, Chen Q, Gao F, Wang J, Long S, Li L, Wu Y, Gao Y, Xu W, Cai X, Qu D, Zhang Z, Zhang H, Li N, Gao Q, Zhang G, He C, Wang W, Ji X, Tang N, Yuan Z, Xie Y, Yang H, Zhang B, Huang A, Jin A Nat Commun. 2021 Nov 2;12(1):6304. doi: 10.1038/s41467-021-26539-7. PMID:34728625[4] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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