8JVA

Cryo-EM structure of the N-terminal domain of Omicron BA.1 in complex with nanobody N235 and S2L20 Fab

Summary for 8JVA

• Entry DOI: 10.2210/pdb8jva/pdb
• EMDB information: 36672
• Descriptor: nanobody N235, S2L20 light chain, S2L20 heavy chain, ... (5 entities in total)
• Functional Keywords: complex, viral protein/immune system, viral protein-immune system complex
• Biological source: Vicugna pacos; More
• Total number of polymer chains: 4
• Total formula weight: 127212.58

Authors

Liu, B.,Liu, H.H.,Han, P.,Qi, J.X. (deposition date: 2023-06-28, release date: 2024-05-22, Last modification date: 2024-11-20)

Primary citation

Liu, B.,Liu, H.,Han, P.,Wang, X.,Wang, C.,Yan, X.,Lei, W.,Xu, K.,Zhou, J.,Qi, J.,Fan, R.,Wu, G.,Tian, W.X.,Gao, G.F.,Wang, Q.
Enhanced potency of an IgM-like nanobody targeting conserved epitope in SARS-CoV-2 spike N-terminal domain.
Signal Transduct Target Ther, 9:131-131, 2024

PubMed Abstract: Almost all the neutralizing antibodies targeting the receptor-binding domain (RBD) of spike (S) protein show weakened or lost efficacy against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) emerged or emerging variants, such as Omicron and its sub-variants. This suggests that highly conserved epitopes are crucial for the development of neutralizing antibodies. Here, we present one nanobody, N235, displaying broad neutralization against the SARS-CoV-2 prototype and multiple variants, including the newly emerged Omicron and its sub-variants. Cryo-electron microscopy demonstrates N235 binds a novel, conserved, cryptic epitope in the N-terminal domain (NTD) of the S protein, which interferes with the RBD in the neighboring S protein. The neutralization mechanism interpreted via flow cytometry and Western blot shows that N235 appears to induce the S1 subunit shedding from the trimeric S complex. Furthermore, a nano-IgM construct (MN235), engineered by fusing N235 with the human IgM Fc region, displays prevention via inducing S1 shedding and cross-linking virus particles. Compared to N235, MN235 exhibits varied enhancement in neutralization against pseudotyped and authentic viruses in vitro. The intranasal administration of MN235 in low doses can effectively prevent the infection of Omicron sub-variant BA.1 and XBB in vivo, suggesting that it can be developed as a promising prophylactic antibody to cope with the ongoing and future infection.

PubMed: 38740785
DOI: 10.1038/s41392-024-01847-8

Experimental method

ELECTRON MICROSCOPY (2.81 Å)