Small molecule-induced allosteric activation of the Vibrio cholerae RTX cysteine protease domain

Vibrio cholerae RTX (repeats in toxin) is an actin-disrupting toxin that is autoprocessed by an internal cysteine protease domain (CPD). The RTX CPD is efficiently activated by the eukaryote-specific small molecule inositol hexakisphosphate (InsP(6)), and we present the 2.1 angstrom structure of the RTX CPD in complex with InsP(6). InsP(6) binds to a conserved basic cleft that is distant from the protease active site. Biochemical and kinetic analyses of CPD mutants indicate that InsP(6) binding induces an allosteric switch that leads to the autoprocessing and intracellular release of toxin-effector domains.