4RGM

Structure of Staphylococcal Enterotoxin B bound to the neutralizing antibody 20B1

Summary for 4RGM

• Entry DOI: 10.2210/pdb4rgm/pdb
• Related: 4RGN 4RGO
• Descriptor: Enterotoxin type B, 20B1 light chain, 20B1 heavy chain, ... (4 entities in total)
• Functional Keywords: neutralizing antibody, staphylococcal enterotoxin b, toxin-immune system complex, toxin/immune system
• Biological source: Staphylococcus aureus; More
• Cellular location: Secreted: P01552
• Total number of polymer chains: 6
• Total formula weight: 153841.98

Authors

Franklin, M.C.,Dutta, K.,Varshney, A.K.,Goger, M.J.,Fries, B.C. (deposition date: 2014-09-30, release date: 2015-01-21, Last modification date: 2024-10-30)

Primary citation

Dutta, K.,Varshney, A.K.,Franklin, M.C.,Goger, M.,Wang, X.,Fries, B.C.
Mechanisms mediating enhanced neutralization efficacy of staphylococcal enterotoxin B by combinations of monoclonal antibodies.
J.Biol.Chem., 290:6715-6730, 2015

PubMed Abstract: Staphylococcal enterotoxin B (SEB) is a superantigen that cross-links the major histocompatibility complex class II and specific V-β chains of the T-cell receptor, thus forming a ternary complex. Developing neutralizing mAb to disrupt the ternary complex and abrogate the resulting toxicity is a major therapeutic challenge because SEB is effective at very low concentrations. We show that combining two SEB-specific mAbs enhances their efficacy, even though one of the two mAbs by itself has no effect on neutralization. Crystallography was employed for fine-mapping conformational epitopes in binary and ternary complexes between SEB and Fab fragments. NMR spectroscopy was used to validate and identify subtle allosteric changes induced by mAbs binding to SEB. The mapping of epitopes established that a combination of different mAbs can enhance efficacy of mAb-mediated protection from SEB induced lethal shock by two different mechanisms: one mAb mixture promoted clearance of the toxin both in vitro and in vivo by FcR-mediated cross-linking and clearance, whereas the other mAb mixture induced subtle allosteric conformational changes in SEB that perturbed formation of the SEB·T-cell receptor·major histocompatibility complex class II trimer. Finally structural information accurately predicted mAb binding to other superantigens that share conformational epitopes with SEB. Fine mapping of conformational epitopes is a powerful tool to establish the mechanism and optimize the action of synergistic mAb combinations.

PubMed: 25572397
DOI: 10.1074/jbc.M114.630715

Experimental method

X-RAY DIFFRACTION (2.689 Å)