9XZX

Staphylococcal Enterotoxin C in complex with NB C107 and NB C112

Summary for 9XZX

• Entry DOI: 10.2210/pdb9xzx/pdb
• EMDB information: 72377
• Descriptor: Enterotoxin type C-2, NB C107, NB C112, ... (4 entities in total)
• Functional Keywords: nanobody, vhh, immune system
• Biological source: Staphylococcus aureus; More
• Total number of polymer chains: 3
• Total formula weight: 53476.16

Authors

Hang, W.,Kim, J.,Taylor, D.J.,Shi, Y. (deposition date: 2025-08-27, release date: 2026-05-06, Last modification date: 2026-06-03)

Primary citation

Kim, Y.J.J.,Walton, N.R.,Huang, W.,Lee, M.,Xiang, Y.,Sang, Z.,Sussman, C.,Moore, S.K.L.,Taylor, D.J.,Chen, K.,Hook, J.L.,McCormick, J.K.,Shi, Y.
Multivalent nanobodies for potent and broad neutralization of Staphylococcus aureus toxins.
Nat Commun, 17:-, 2026

PubMed Abstract: Staphylococcus aureus is a leading cause of lethal bacteremia and pneumonia, which are driven by potent virulence factors such as T-cell superantigens and alpha hemolysin. S. aureus has among the highest rates of antibiotic resistance, yet no vaccines or alternative therapies are available. Here, we developed a repertoire of potent, high-affinity nanobodies (Nbs) targeting key toxins in S. aureus infection, including Hla and superantigens SEB, SEC, and TSST-1. Comprehensive cryo-EM and AlphaFold3 analyses of these Nbs, which were elicited with clinical cocktail vaccines, revealed diverse neutralizing epitopes and mechanisms that provide insights for immunotherapy and vaccine strategies. Guided by these findings, we engineered stable, multivalent, and multifunctional Nb constructs. These constructs included an aerosolizable trimeric Nb with enhanced neutralization activity against Hla and SEC, and a decameric Nb-IgG-Fc fusion construct with pM or better potencies against a wide range of major toxins in S. aureus sepsis (SEB, SEC, TSST-1, and Hla). These multifunctional Nbs demonstrated protective activity in murine models of pneumonia and sepsis, underscoring their potential as versatile immunotherapies that address the complex virulence of S. aureus. Our work lays a foundation for precision immunotherapies beyond current treatment options to combat complex bacterial infections with multiple virulence mechanisms.

PubMed: 42161902
DOI: 10.1038/s41467-026-73120-1

Experimental method

ELECTRON MICROSCOPY (3.1 Å)