9UPR

Cryo-EM structure of the N-terminal domain of Omicron BA.1 in complex with nanobody N103 and S2L20 Fab

Summary for 9UPR

• Entry DOI: 10.2210/pdb9upr/pdb
• EMDB information: 64401
• Descriptor: S2L20 light chain, S2L20 heavy chain, nanobody N103, ... (6 entities in total)
• Functional Keywords: complex, viral protein/immune system, viral protein-immune system complex, viral protein
• Biological source: Homo sapiens; More
• Total number of polymer chains: 4
• Total formula weight: 127237.54

Authors

Liu, B.,Liu, H.H.,Wang, C.M.,Han, P.,Wang, Q.H. (deposition date: 2025-04-28, release date: 2026-05-06, Last modification date: 2026-06-10)

Primary citation

Tian, X.,Wang, C.,Han, P.,Liu, H.,Wu, L.,Wang, X.,Yu, S.,Zhang, Y.,Zhao, B.,Liu, J.,Gao, G.F.,Wang, Q.
From weak but broad to potent and universal: A trispecific antibody against conserved SARS-CoV-2 spike epitopes.
Mol.Ther., 2026

PubMed Abstract: Most neutralizing antibodies against severe acute respiratory syndrome coronavirus 2 target the receptor-binding domain (RBD). However, due to high immune pressure, the RBD accumulates mutations, thus significantly reducing antibody efficacy against emerging variants/subvariants. Although some RBD-targeting antibodies bind conserved epitopes, they usually exhibit weak-to-moderate neutralization. Similarly, antibodies against the N-terminal domain (NTD) or S2 subunit often retain broad binding but generally lack potent neutralization. To address this, we initially identified the broadly reactive nanobody, N103, which exhibited weak neutralizing potency. Structural and functional analyses revealed that N103 targets a conserved NTD epitope and triggers S1 subunit shedding, thereby destabilizing the spike trimer through an allosteric mechanism. Leveraging this insight, we engineered a trispecific antibody combining N103 with antibodies targeting the conserved RBD and S2 epitopes. This design synergistically integrated their distinct binding profiles and mechanisms, achieving potent and broad neutralization against both pseudoviruses and authentic viruses, including the immune-evasive BA.2.86 subvariant. Furthermore, challenge studies in human angiotensin-converting enzyme 2 knockin mice demonstrated robust in vivo protection. Our findings highlight a cooperative multi-target strategy in which antibodies with limited individual potency can collectively achieve broad and potent neutralization through rational design. This approach provides a promising framework for next-generation antibody therapeutics.

PubMed: 42186224
DOI: 10.1016/j.ymthe.2026.05.012

Experimental method

ELECTRON MICROSCOPY (2.77 Å)