The botulinum neurotoxins are the most toxic substances known; they are one million times more toxic than the cobra toxin. In spite of their extreme toxicity there has been a rapid expansion of the medical applications for the botulinum neurotoxins, with new applications constantly being discovered. This line of treatment is becoming the standard procedure for many conditions. The toxins are possible agents for bioterrorism and the development of countermeasures and vaccines are of high priority. We are studying the toxins using a wide variety of methods, including X-ray crystallography and cryo-EM to understand the toxins basic mechanism and to improve their therapeutic properties.
We also study enzymes involved in the nucleotide metabolism. One example is MTH1, this protein is important for clearing oxidative damage from the nucleotide pool. Many types of cancer cells have high levels of oxidative damage and depend on MTH1 for survival. We use X-ray crystallography to study the binding of MTH1 to natural substrates and potent inhibitors that we are developing in an interdisciplinary research collaboration. We use structural based drug design to refine these inhibitors into novel cancer drugs.