7x8w | pdb_00007x8w
The SARS-CoV-2 receptor binding domain bound with the Fab fragment of a human neutralizing antibody Ab354
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 PubMedThe use of therapeutic neutralizing antibodies against SARS-CoV-2 infection has been highly effective. However, there remain few practical antibodies against viruses that are acquiring mutations. In this study, we created 494 monoclonal antibodies from patients with COVID-19-convalescent, and identified antibodies that exhibited the comparable neutralizing ability to clinically used antibodies in the neutralization assay using pseudovirus and authentic virus including variants of concerns. These antibodies have different profiles against various mutations, which were confirmed by cell-based assay and cryo-electron microscopy. To prevent antibody-dependent enhancement, N297A modification was introduced. Our antibodies showed a reduction of lung viral RNAs by therapeutic administration in a hamster model. In addition, an antibody cocktail consisting of three antibodies was also administered therapeutically to a macaque model, which resulted in reduced viral titers of swabs and lungs and reduced lung tissue damage scores. These results showed that our antibodies have sufficient antiviral activity as therapeutic candidates. Potent SARS-CoV-2 neutralizing antibodies with therapeutic effects in two animal models.,Takeshita M, Fukuyama H, Kamada K, Matsumoto T, Makino-Okamura C, Uchikubo-Kamo T, Tomabechi Y, Hanada K, Moriyama S, Takahashi Y, Ishigaki H, Nakayama M, Nguyen CT, Kitagawa Y, Itoh Y, Imai M, Maemura T, Furusawa Y, Ueki H, Iwatsuki-Horimoto K, Ito M, Yamayoshi S, Kawaoka Y, Shirouzu M, Ishii M, Saya H, Kondo Y, Kaneko Y, Suzuki K, Fukunaga K, Takeuchi T iScience. 2022 Dec 22;25(12):105596. doi: 10.1016/j.isci.2022.105596. Epub 2022 , Nov 15. PMID:36406861[4] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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