Crystallographic studies of the anthrax lethal toxin

Area of Science:

• Structural biology
• Molecular toxicology
• Bacterial pathogenesis

Background:

• Anthrax lethal toxin consists of protective antigen (PA) and lethal factor (LF).
• PA forms a heptameric pore for LF translocation into host cells.
• Understanding toxin structure is crucial for developing countermeasures.

Purpose of the Study:

• To elucidate the three-dimensional structure of protective antigen (PA).
• To investigate the mechanism of PA-mediated membrane insertion.
• To present progress on the structural determination of lethal factor (LF) and the PA-LF translocation complex.

Main Methods:

• X-ray crystallography was used to determine the structure of PA in monomeric and heptameric forms.
• Proposed a model for pH-induced conformational changes during membrane insertion.
• Progress in crystallizing LF and the PA-LF complex.

Main Results:

• The crystal structure of PA revealed a novel structural class of bacterial toxins.
• A model for PA membrane insertion involving a 14-stranded beta-barrel was proposed and supported by experimental data.
• Significant progress has been made towards atomic resolution structures of LF and the translocation complex.

Conclusions:

• PA represents a new structural class of toxins, distinct from previously characterized bacterial toxins.
• The proposed membrane insertion model provides insights into toxin entry mechanisms.
• Structural insights into LF and the translocation complex are expected to advance understanding of anthrax pathogenesis.