7ttm
Crystal structure of potent neutralizing antibody 10-40 in complex with Sarbecovirus bat SHC014 receptor-binding domain
Structural highlights
FunctionU5WLK5_SARS Spike protein S1: attaches the virion to the cell membrane by interacting with host receptor, initiating the infection.[HAMAP-Rule:MF_04099] Spike protein S2': Acts as a viral fusion peptide which is unmasked following S2 cleavage occurring upon virus endocytosis.[HAMAP-Rule:MF_04099] Spike protein S2: 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] Publication Abstract from PubMedThe devastation caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has made clear the importance of pandemic preparedness. To address future zoonotic outbreaks due to related viruses in the sarbecovirus subgenus, we identified a human monoclonal antibody, 10-40, that neutralized or bound all sarbecoviruses tested in vitro and protected against SARS-CoV-2 and SARS-CoV in vivo. Comparative studies with other receptor-binding domain (RBD)-directed antibodies showed 10-40 to have the greatest breadth against sarbecoviruses, suggesting that 10-40 is a promising agent for pandemic preparedness. Moreover, structural analyses on 10-40 and similar antibodies not only defined an epitope cluster in the inner face of the RBD that is well conserved among sarbecoviruses but also uncovered a distinct antibody class with a common CDRH3 motif. Our analyses also suggested that elicitation of this class of antibodies may not be overly difficult, an observation that bodes well for the development of a pan-sarbecovirus vaccine. An antibody class with a common CDRH3 motif broadly neutralizes sarbecoviruses.,Liu L, Iketani S, Guo Y, Reddem ER, Casner RG, Nair MS, Yu J, Chan JF, Wang M, Cerutti G, Li Z, Morano NC, Castagna CD, Corredor L, Chu H, Yuan S, Poon VK, Chan CC, Chen Z, Luo Y, Cunningham M, Chavez A, Yin MT, Perlin DS, Tsuji M, Yuen KY, Kwong PD, Sheng Z, Huang Y, Shapiro L, Ho DD Sci Transl Med. 2022 May 25;14(646):eabn6859. doi: 10.1126/scitranslmed.abn6859. , Epub 2022 May 25. PMID:35438546[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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