Opportunistic pathogens exploit diverse strategies to sabotage host defenses. Pseudomonas aeruginosa secretes the CFTR inhibitory factor Cif and thus triggers loss of CFTR, an ion channel required for airway mucociliary defense. However, the mechanism of action of Cif has remained unclear. It catalyzes epoxide hydrolysis, but there is no known role for natural epoxides in CFTR regulation. It was demonstrated that the hydrolase activity of Cif is strictly required for its effects on CFTR. A small-molecule inhibitor that protects this key component of the mucociliary defense system was also uncovered. These results provide a basis for targeting the distinctive virulence chemistry of Cif and suggest an unanticipated role of physiological epoxides in intracellular protein trafficking.
Representative scheme of CFTR-inhibitory-factor_Cif structure and an image from PDBsum server
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Databases
PDB-Sum
4DM7 Previously Class, Architecture, Topology and Homologous superfamily - PDB-Sum server
FSSP
4DM7Fold classification based on Structure-Structure alignment of Proteins - FSSP server
