Model of the toxic complex of anthrax: Responsive conformational changes in both the lethal factor and the protective antigen heptamer

The toxic complex of anthrax is formed when the monomeric protective antigen (PA) (83 kDa), while bound to its cell‐surface receptor, is first converted to PA63 heptamers (PA63h) following N‐terminal proteolytic cleavage, and then lethal (LF) (90 kDa) or edema factor (EF) binds to the heptamer. We report a “pseudoatomic” model for the complex of PA63h and full‐length LF determined by applying the normal‐mode flexible fitting procedure to a ∼18 Å cryo‐electron microscopy (EM) density map of the complex. The model describes the interacting surface that buries a total area of ∼10,140 Å 2 comprising ∼40% charged, and ∼30% each of polar and hydrophobic residues. For the heptamer, the buried surface, composed of ∼110 residues, involves primarily three monomers and includes for two, similar stretches of the polypeptide chain from domain 1. For LF, the interface again involves ∼110 residues, mostly from the N‐terminal domain I (LF N ), and the structurally homologous C‐terminal domain IV. Most interestingly, bound LF displays a marked conformational change resulting from a “collapse” of domains I, III, and IV on domain II, with the largest movement of ∼9 Å noted for domain I. On the other hand, primarily, rigid‐body movements, larger than ∼10 Å for three PA63 monomers, cause the hourglass‐shaped heptamer lumen to enlarge by as much as ∼50% near the middle of the molecule. Such concerted structural rearrangements in LF and the heptamer can facilitate ingress of the ligand into the heptamer lumen prior to unfolding and release through the PA63h channel formed in the acidic late endosomal membrane.