title: Structural basis for the neutralization and specificity of Staphylococcal enterotoxin B against its MHC Class II binding site.
abstract: Staphylococcal enterotoxin (SE) B is among the potent toxins produced by Staphylococcus aureus that cause toxic shock syndrome (TSS), which can result in multi-organ failure and death. Currently, neutralizing antibodies have been shown to be effective immunotherapeutic agents against this toxin, but the structural basis of the neutralizing mechanism is still unknown. In this study, we generated a neutralizing monoclonal antibody, 3E2, against SEB, and analyzed the crystal structure of the SEB-3E2 Fab complex. Crystallographic analysis suggested that the neutralizing epitope overlapped with the MHC II molecule binding site on SEB, and thus 3E2 could inhibit SEB function by preventing interaction with the MHC II molecule. Mutagenesis studies were done on SEB, as well as the related Staphylococcus aureus toxins SEA and SEC. These studies revealed that tyrosine (Y)46 and lysine (K)71 residues of SEB are essential to specific antibody-antigen recognition and neutralization. Substitution of Y at SEA glutamine (Q)49, which corresponds to SEB Y46, increased both 3E2's binding to SEA in vitro and the neutralization of SEA in vivo. These results suggested that SEB Y46 is responsible for distinguishing SEB from SEA. These findings may be helpful for the development of antibody-based therapy for SEB-induced TSS.
authors.affiliation: International Joint Cancer Institute; Second Military Medical University; Shanghai, P.R. China; College of Pharmacy; Liaocheng University; Liaocheng, P.R. China.
authors.forename: Tian
authors.initials: T
authors.lastname: Xia
authors.affiliation: Laboratory of Structural Biology and MOE Laboratory of Protein Science; School of Medicine and Life Science; Tsinghua University; Beijing, P.R. China.
authors.forename: Shuaiyi
authors.initials: S
authors.lastname: Liang
authors.affiliation: International Joint Cancer Institute; Second Military Medical University; Shanghai, P.R. China; State Key Laboratory of Antibody Medicine and Targeting Therapy and Shanghai Key Laboratory of Cell Engineering and Antibody; Shanghai, P.R. China.
authors.forename: Huajing
authors.initials: H
authors.lastname: Wang
authors.affiliation: International Joint Cancer Institute; Second Military Medical University; Shanghai, P.R. China; State Key Laboratory of Antibody Medicine and Targeting Therapy and Shanghai Key Laboratory of Cell Engineering and Antibody; Shanghai, P.R. China.
authors.forename: Shi
authors.initials: S
authors.lastname: Hu
authors.affiliation: National Laboratory of Macromolecules; Institute of Biophysics; Chinese Academy of Science; Beijing, P.R. China.
authors.forename: Yuna
authors.initials: Y
authors.lastname: Sun
authors.affiliation: International Joint Cancer Institute; Second Military Medical University; Shanghai, P.R. China; State Key Laboratory of Antibody Medicine and Targeting Therapy and Shanghai Key Laboratory of Cell Engineering and Antibody; Shanghai, P.R. China.
authors.forename: Xiaojie
authors.initials: X
authors.lastname: Yu
authors.affiliation: College of Pharmacy; Liaocheng University; Liaocheng, P.R. China.
authors.forename: Jun
authors.initials: J
authors.lastname: Han
authors.affiliation: College of Pharmacy; Liaocheng University; Liaocheng, P.R. China.
authors.forename: Jun
authors.initials: J
authors.lastname: Li
authors.affiliation: College of Pharmacy; Liaocheng University; Liaocheng, P.R. China.
authors.forename: Shangjing
authors.initials: S
authors.lastname: Guo
authors.affiliation: International Joint Cancer Institute; Second Military Medical University; Shanghai, P.R. China; State Key Laboratory of Antibody Medicine and Targeting Therapy and Shanghai Key Laboratory of Cell Engineering and Antibody; Shanghai, P.R. China; College of Pharmacy; Liaocheng University; Liaocheng, P.R. China.
authors.forename: Jianxin
authors.initials: J
authors.lastname: Dai
authors.affiliation: Laboratory of Structural Biology and MOE Laboratory of Protein Science; School of Medicine and Life Science; Tsinghua University; Beijing, P.R. China.
authors.forename: Zhiyong
authors.initials: Z
authors.lastname: Lou
authors.affiliation: International Joint Cancer Institute; Second Military Medical University; Shanghai, P.R. China; State Key Laboratory of Antibody Medicine and Targeting Therapy and Shanghai Key Laboratory of Cell Engineering and Antibody; Shanghai, P.R. China; College of Pharmacy; Liaocheng University; Liaocheng, P.R. China.
authors.forename: Yajun
authors.initials: Y
authors.lastname: Guo
mesh_terms: D000818:Animals; D000907:Antibodies, Bacterial / Q000276:immunology* / Q000627:therapeutic use; D058846:Antibodies, Monoclonal, Murine-Derived / Q000378:metabolism* / Q000627:therapeutic use; D057134:Antibodies, Neutralizing / Q000276:immunology* / Q000627:therapeutic use; D001426:Bacterial Proteins / Q000235:genetics / Q000276:immunology*; D001665:Binding Sites; D004768:Enterotoxins / Q000235:genetics / Q000276:immunology*; D000949:Histocompatibility Antigens Class II / Q000235:genetics / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D016297:Mutagenesis, Site-Directed; D012772:Shock, Septic / Q000188:drug therapy / Q000276:immunology
chemical_list: D000907:Antibodies, Bacterial; D058846:Antibodies, Monoclonal, Murine-Derived; D057134:Antibodies, Neutralizing; D001426:Bacterial Proteins; D004768:Enterotoxins; D000949:Histocompatibility Antigens Class II; C031818:enterotoxin B, staphylococcal
keywords: Staphylococcus aureus; crystal structure; enterotoxin B; mechanism; neutralizing antibody