Small Molecule-Induced Allosteric Activation of the Vibrio cholerae RTX Cysteine Protease Domain

摘要

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.