8hpu
From Proteopedia
Cryo-EM structure of SARS-CoV-2 Omicron BA.4 RBD in complex with fab L4.65 and L5.34
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 PubMedVaccination with different vaccines has been implemented globally to counter the continuous COVID-19 pandemic. However, the vaccine-elicited antibodies have reduced efficiency against the highly mutated Omicron sub-variants. Previously, we developed a protein subunit COVID-19 vaccine called ZF2001, based on the dimeric receptor-binding domain (RBD). This vaccine has been administered using different dosing intervals in real-world setting. Some individuals received three doses of ZF2001, with a one-month interval between each dose, due to urgent clinical requirements. Others had an extended dosing interval of up to five months between the second and third dose, a standard vaccination regimen for the protein subunit vaccine against hepatitis B. In this study, we profile B cell responses in individuals who received three doses of ZF2001, and compared those with long or short dosing intervals. We observed that the long-interval group exhibited higher and broader serologic antibody responses. These responses were associated with the increased size and evolution of vaccine-elicited B-cell receptor repertoires, characterized by the elevation of expanded clonotypes and somatic hypermutations. Both groups of individuals generated substantial amounts of broadly neutralizing antibodies (bnAbs) against various SARS-CoV-2 variants, including Omicron sub-variants such as XBB. These bnAbs target four antigenic sites within the RBD. To determine the vulnerable site of SARS-CoV-2, we employed cryo-electron microscopy to identify the epitopes of highly potent bnAbs that targeted two major sites. Our findings provide immunological insights into the B cell responses elicited by RBD-based vaccine, and suggest that a vaccination regimen of prolonging time interval should be used in practice. Dosing interval regimen shapes potency and breadth of antibody repertoire after vaccination of SARS-CoV-2 RBD protein subunit vaccine.,Guo S, Zheng Y, Gao Z, Duan M, Liu S, Du P, Xu X, Xu K, Zhao X, Chai Y, Wang P, Zhao Q, Gao GF, Dai L Cell Discov. 2023 Jul 28;9(1):79. doi: 10.1038/s41421-023-00585-5. PMID:37507370[4] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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