Allosterically switchable network orients <i>β</i>-flap in <i>Clostridioides difficile</i> toxins.

ABSTRACT: Allosteric proteins exhibit a functional response upon ligand binding far from the active site. Clostridioides difficile toxins use allosteric binding by the endogenous cofactor myo-inositol hexakisphosphate to orchestrate self-cleavage from within the target cell. This binding event induces a conformational shift, primarily effecting a lever-like β-flap region, with two known orientations. We uncovered a mechanism for this allosteric transition using extensive atomistic molecular dynamics simulations and computational and experimental mutagenesis. The mechanism relies on a switchable interaction network. The most prominent interaction pair is K600-E743, with K600 interactions explaining ∼70% of the allosteric effect. Rather than gradually morphing between two end stat

SUBMITTER: Finn LM 

PROVIDER: S-EPMC12002228 | biostudies-literature | 2025 Apr

REPOSITORIES: biostudies-literature