9HLS

Structure of A16/G9 (vaccinia virus) in complex with VHH D07, VHH B01 and VHH C05

Summary for 9HLS

• Entry DOI: 10.2210/pdb9hls/pdb
• Descriptor: Virion membrane protein OPG143, Entry-fusion complex protein OPG094, VHH D07, ... (8 entities in total)
• Functional Keywords: poxvirus, viral fusion, vaccinia virus, mpox virus, viral protein
• Biological source: Vaccinia virus Western Reserve; More
• Total number of polymer chains: 10
• Total formula weight: 259537.43

Authors

Vernuccio, R.,Meola, A.,Guardado-Calvo, P. (deposition date: 2024-12-05, release date: 2025-09-03, Last modification date: 2025-11-12)

Primary citation

Meola, A.,Vernuccio, R.,Battini, L.,Albericio, G.,Delgado, P.,Bamford, R.,Pokorny, L.,Broutin, M.,Martinez Leon, A.,Gallien, S.,Gil, M.,Noriega, M.A.,Guivel-Benhassine, F.,Porrot, F.,Postal, J.,Buchrieser, J.,Hubert, M.,Haouz, A.,Lafaye, P.,Esteban, M.,Hub, J.S.,Mahevas, M.,Chappert, P.,Mercer, J.,Garcia-Arriaza, J.,Schwartz, O.,Guardado-Calvo, P.
Structural basis of poxvirus fusion regulation and anti-A16/G9 antibody-mediated neutralization and protection.
Cell, 188:6266-, 2025

PubMed Abstract: Monkeypox virus (MPXV) is a poxvirus endemic to Central and West Africa with high epidemic potential. Poxviruses enter host cells via a conserved entry-fusion complex (EFC), which mediates viral fusion to the cell membrane. The EFC is a promising therapeutic target, but the absence of structural data has limited the development of fusion-inhibiting treatments. Here, we investigated A16/G9, a subcomplex of the EFC that controls fusion timing. Using cryo-electron microscopy, we showed how A16/G9 interacts with A56/K2, a viral fusion suppressor that prevents superinfection. Immunization with A16/G9 elicited a protective immune response in mice. Using X-ray crystallography, we characterized two neutralizing antibodies and engineered a chimeric antibody that cross-neutralizes several poxviruses more efficiently than 7D11, the most potent antibody targeting the EFC described to date. These findings highlight the potential of A16/G9 as a candidate for subunit vaccines and identify regions of the EFC as targets for antiviral development.

PubMed: 40865523
DOI: 10.1016/j.cell.2025.07.040

Experimental method

X-RAY DIFFRACTION (3.2 Å)