The conformation of the third component that makes up the 'anthrax toxin', odema factor (EF), is considerably altered upon binding to calmodulin.
Knowledge of the structure of the proteins that make up 'anthrax toxin' should be valuable in the design of new drugs to counteract its lethal effects. Two of the three toxin components, protective antigen and lethal factor, had their structures determined in 1997 and 2001, respectively. In the January 24 issue of Nature, Drum et al. now complete the story by elucidating the structure of the third component, oedema factor (EF), with and without calmodulin (CaM), the protein that activates EF after entry into the host cell.
Like many infectious organisms, the anthrax bacteria disrupts intracellular signalling pathways by increasing the concentration of a key signalling molecule — cyclic AMP — in infected cells, thus inhibiting the immune response against the bacteria. On binding to calmodulin, a ubiquitous intracellular modulator, the conformation of EF is considerably altered, creating a site that can catalyse the formation of cAMP from ATP, but at a rate 1,000-fold higher than that of the adenylyl-cyclase–CaM complex that has this role in normal cells. Moreover, in the EF–CaM complex, CaM is locked into a conformation that cannot modulate other signalling proteins, as it would normally.
Whether or not EF represents a good drug target remains to be seen; however, its active site is a deep, narrow pocket that should be amenable to blocking with a small molecule, and also differs considerably from the active site of mammalian adenylyl cyclase, reducing the risk of adverse interference with this key enzyme. Further research could also have benefits beyond the potential for anthrax therapies, as EF-like adenylyl-cyclase toxins are found in pathogens that cause whooping cough and common hospital-acquired infections.
Peter Kirkpatrick
References
ORIGINAL RESEARCH PAPER Drum, C. L. et al. Structural basis for the activation of anthrax adenlyl cyclase exotoxin by calmodulin. Nature415, 317–402 (2002)
FURTHER READING Petosa, C. et al. Crystal structure of the anthrax toxin protective antigen. Nature385, 833–838 (1997) | PubMed |
Pannifer, A. D. et al. Crystal structure of the anthrax lethal factor. Nature414, 229–233 (2001) | Article | PubMed |
