THE CRYSTAL-STRUCTURE OF PERTUSSIS TOXIN

Background: Pertussis toxin is an exotoxin of the A-B class produced b y Bordetella pertussis. The holotoxin comprises 952 residues forming s ix subunits (five different sequences, S1-S5). It plays an important r ole in the development of protective immunity to whooping cough, and i s an essential component of new acellular vaccines. It is also widely used as a biochemical tool to ADP-ribosylate GTP-binding proteins in t he study of signal transduction. Results: The crystal structure of per tussis toxin has been determined at 2.3 Angstrom resolution. The catal ytic A-subunit (S1) shares structural homology with other ADP-ribosyla ting bacterial toxins, although differences in the carboxy-terminal po rtion explain its unique activation mechanism. Despite its heterogeneo us subunit composition, the structure of the cell-binding B-oligomer ( S2, S3, two copies of S4, and S5) resembles the symmetrical B-pentamer s of the cholera toxin and Shiga toxin families, but it interacts diff erently with the A-subunit. The structural similarity is all the more surprising given that there is almost no sequence homology between B-s ubunits of the different toxins. Two peripheral domains that are uniqu e to the pertussis toxin B-oligomer show unexpected structural homolog y with a calcium-dependent eukaryotic lectin, and reveal possible rece ptor-binding sites. Conclusion: The structure provides insight into th e pathogenic mechanisms of pertussis toxin and the evolution of bacter ial toxins. Knowledge of the tertiary structure of the active site for ms a rational basis for elimination of catalytic activity in recombina nt molecules for vaccine use.