Abstract
Integrins are ubiquitous cell-surface heterodimers that are exploited by pathogens and toxins, including leukotoxins that target β2 integrins on phagocytes. The Bordetella adenylate cyclase toxin (ACT) uses the αMβ2 integrin as a receptor, but the structural basis for integrin binding and neutralization by antibodies is poorly understood. Here, we use cryoelectron microscopy to determine a 2.7 Å resolution structure of an ACT fragment bound to αMβ2. This structure reveals that ACT interacts with the headpiece and calf-2 of the αM subunit in a non-canonical manner specific to bent, inactive αMβ2. Neutralizing antibody epitopes map to ACT residues involved in αM binding, providing the basis for antibody-mediated attachment inhibition. Furthermore, binding to αMβ2 positions the essential ACT acylation sites, which are conserved among toxins exported by type I secretion systems, at the cell membrane. These findings reveal a structural mechanism for integrin-mediated attachment and explain antibody-mediated neutralization of ACT intoxication.