Molecular basis for bordetella pertussis interference with complement, coagulation, fibrinolytic, and contact activation systems: The cryo-em structure of the vag8-c1 inhibitor complex

Complement, contact activation, coagulation, and fibrinolysis are serum protein cascades that need strict regulation to maintain human health. Serum glyco-protein, a C1 inhibitor (C1-INH), is a key regulator (inhibitor) of serine proteases of all the above-mentioned pathways. Recently, an autotransporter protein, virulence-asso-ciated gene 8 (Vag8), produced by the whooping cough pathogen, Bordetella pertus-sis, was shown to bind to C1-INH and interfere with its function. Here, we present the structure of the Vag8–C1-INH complex determined using cryo-electron microscopy at a 3.6-Å resolution. The structure shows a unique mechanism of C1-INH inhibition not employed by other pathogens, where Vag8 sequesters the reactive center loop of C1-INH, preventing its interaction with the target proteases