Ajda KrcPhD student

Understanding Structures of bacterial exotoxins

Bacterial exotoxins are secreted in a course of bacterial infections and are known to cause various serious diseases, such as tetanus, cholera, diphtheria, or botulism. The toxins are produced by bacteria and target some of the most important functions in the body of affected organisms. They can selectively target only certain types of cells (for example botulinum neurotoxin targets only neuronal cells) or can affect all cells indiscriminately (like in the case of diphtheria toxin). Despite being the most potent “poisons” known to man, some of the exotoxins are used for medical as well as cosmetic purposes. Botulinum neurotoxin for example is well-known by its commercial name Botox and is also used for the treatment of involuntary muscle movement (spasticity), as it acts specifically at the neuro-muscular junction inhibiting the signal progression. Diphtheria toxin on the other hand is a very potent toxin targeting the protein synthesis pathway in all cells of the body. There are already FDA-approved cancer drugs, so-called immunotoxins that contain an active domain of diphtheria toxin, successfully killing malignant cells.

The most powerful exotoxins all belong to the same structural family of A-B toxins with a distinct two-domain structure architecture. In fact, the structural features of these toxins enable their very specific and efficient mechanism of action. Therefore, structure determination, in combination with the biochemical and biophysical characterization of these proteins, is crucial for understanding their underlying mechanisms of toxicity as well as for structure-guided design of new therapeutics. 

My PhD projects focus on two important classes of bacterial exotoxins, namely botulinum neurotoxins and diphtheria-like toxins. We aim to solve the structures of different members of the two classes and other proteins that are involved in the toxicity of these exotoxins using X-ray crystallography and cryo-electron microscopy. We also perform other standard biochemical and biophysical analyses to characterize the proteins in terms of their stability, substrate specificity, binding modes, etc.

Figure shows the general toxicity pathway of exotoxins.

Research group: Pål Stenmark