title: Anthrax toxin-neutralizing antibody reconfigures the protective antigen heptamer into a supercomplex.
abstract: The tripartite protein exotoxin secreted by Bacillus anthracis, a major contributor to its virulence and anthrax pathogenesis, consists of binary complexes of the protective antigen (PA) heptamer (PA63h), produced by proteolytic cleavage of PA, together with either lethal factor or edema factor. The mouse monoclonal anti-PA antibody 1G3 was previously shown to be a potent antidote that shares F(C) domain dependency with the human monoclonal antibody MDX-1303 currently under clinical development. Here we demonstrate that 1G3 instigates severe perturbation of the PA63h structure and creates a PA supercomplex as visualized by electron microscopy. This phenotype, produced by the unconventional mode of antibody action, highlights the feasibility for optimization of vaccines based on analogous structural modification of PA63h as an additional strategy for future remedies against anthrax.
authors.affiliation: School of Biological Sciences, University of Auckland, 1010 Auckland, New Zealand.
authors.forename: Mazdak
authors.initials: M
authors.lastname: Radjainia
authors.forename: Jae-Kyung
authors.initials: JK
authors.lastname: Hyun
authors.forename: Clinton E
authors.initials: CE
authors.lastname: Leysath
authors.forename: Stephen H
authors.initials: SH
authors.lastname: Leppla
authors.forename: Alok K
authors.initials: AK
authors.lastname: Mitra
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal; D057134:Antibodies, Neutralizing; D000936:Antigen-Antibody Complex / Q000737:chemistry*; D000942:Antigens, Bacterial / Q000737:chemistry* / Q000276:immunology*; D001427:Bacterial Toxins / Q000737:chemistry* / Q000276:immunology*; D006801:Humans; D051379:Mice; D011487:Protein Conformation; D055503:Protein Multimerization
chemical_list: D000911:Antibodies, Monoclonal; D057134:Antibodies, Neutralizing; D000936:Antigen-Antibody Complex; D000942:Antigens, Bacterial; D001427:Bacterial Toxins; C030325:anthrax toxin