9WDP

Cyro-EM structure of prefusion RSV fusion glycoprotein in complex with Ziresovir and motavizumab Fab

This is a non-PDB format compatible entry.

Summary for 9WDP

• Entry DOI: 10.2210/pdb9wdp/pdb
• EMDB information: 65894
• Descriptor: Fusion glycoprotein F0,Fibritin, Motavizumab Fab heavy chain, Motavizumab Fab light chain, ... (4 entities in total)
• Functional Keywords: inhibitor, complex, viral protein/immune system, viral protein-immune system complex
• Biological source: Human respiratory syncytial virus A2; More
• Total number of polymer chains: 9
• Total formula weight: 339147.84

Authors

Zhang, W.,Yan, M.R.,Zou, J.J.,Peng, W. (deposition date: 2025-08-19, release date: 2026-01-14, Last modification date: 2026-07-29)

Primary citation

Yan, M.,Zou, J.,Gao, Z.,Yuan, H.,Wu, J.Z.,Zou, G.,Liu, F.,Peng, W.
Molecular mechanism of ziresovir targeting the fusion glycoprotein of respiratory syncytial virus.
Plos Pathog., 22:e1013864-e1013864, 2026

PubMed Abstract: Respiratory syncytial virus (RSV) is a leading cause of lower respiratory tract infections in infants and the elderly worldwide. Although prophylactic monoclonal antibodies and RSV vaccines are available for preventing severe RSV infection, unmet medical need remains for an effective antiviral agent to treat patients who do not benefit from these interventions. Ziresovir (formerly AK0529) is a potent, selective, and orally bioavailable RSV fusion inhibitor with proved antiviral efficacy and clinical benefits. To understand the molecular mechanism of action, we computationally modeled ziresovir with the RSV fusion (F) protein. Here, we present a cryo-EM structure of the RSV F protein-ziresovir complex, elucidating the molecular interactions underlying the drug binding, revealing ziresovir specifically binds to the central cavity within the metastable prefusion conformation of RSV F protein. Leveraging this structural insight, we engineered site-directed RSV mutants guided by both the cryo-EM binding model and drug-resistant RSV variants for fusion inhibitors identified in vitro, and demonstrated that these resistant viruses do not replicate as efficient as wild-type RSV and indicated a fitness cost for viral escape from drug treatment. Collectively, these findings unveil the structural mechanism of ziresovir-mediated viral inhibition, providing a framework for developing the next-generation RSV fusion inhibitors.

PubMed: 41576151
DOI: 10.1371/journal.ppat.1013864

Experimental method

ELECTRON MICROSCOPY (3.27 Å)