9UAA

Nipah virus fusion glycoprotein in complex with a broadly neutralizing antibody 5C8

Replaces:  8XNH

Summary for 9UAA

• Entry DOI: 10.2210/pdb9uaa/pdb
• EMDB information: 63983
• Descriptor: Fusion glycoprotein F0, 5C8-VL, 5C8-VH, ... (5 entities in total)
• Functional Keywords: henipavirus, fusion glycoprotein, antibody, antiviral protein, viral protein, viral protein-immune system complex, viral protein/immune system
• Biological source: Henipavirus nipahense; More
• Total number of polymer chains: 9
• Total formula weight: 224963.64

Authors

Fan, P.F.,Ren, Y.,Yu, C.M.,Chen, W. (deposition date: 2025-03-31, release date: 2025-04-09, Last modification date: 2025-10-22)

Primary citation

Ren, Y.,Fan, P.,Zhang, X.,Fang, T.,Chen, Z.,Yao, Y.,Chi, X.,Zhang, G.,Zhao, X.,Sun, B.,Li, F.,Liu, Z.,Song, Z.,Zhang, B.,Peng, C.,Li, E.,Yang, Y.,Li, J.,Chiu, S.,Yu, C.
Potent Cross-neutralizing Antibodies Reveal Vulnerabilities of Henipavirus Fusion Glycoprotein.
Adv Sci, 12:e2501996-e2501996, 2025

PubMed Abstract: Hendra and Nipah viruses (HNVs), zoonotic paramyxoviruses with >50% case fatality rates, cause fatal encephalitis and respiratory disease, yet lack approved therapies. Here, nine rhesus-derived monoclonal antibodies (mAbs) targeting the fusion glycoprotein (F) prefusion conformation are developed. Four mAbs exhibit first-rate cross-neutralization against HNVs, with two showing synergistic potency when combined with attachment glycoprotein (G)-specific mAbs. Single-dose administration of mAbs confers robust protection against lethal Nipah virus challenge in hamsters. Structural insights reveal that 8 of the 9 potent mAbs adopt a human IGHV4-59-like framework with protruding CDRH3 loops, forming pushpin-shaped paratopes that stabilize the prefusion F-trimer by occupying vulnerable interprotomer cavities. Systematic mutational profiling identifies 14 prefusion-locking residues within the F ectodomain, classified as i) structural linchpins governing fusogenicity or ii) immunodominant hotspots targeted by cross-neutralizing mAbs. This work delivers promising therapeutic candidates against HNVs and provides blueprints for the rational design of antibodies and vaccines targeting viral fusion machinery.

PubMed: 40298900
DOI: 10.1002/advs.202501996

Experimental method

ELECTRON MICROSCOPY (2.22 Å)