Crystallographic evidence for doxorubicin binding to the receptor-binding site in Clostridium botulinum neurotoxin B

The neurotoxins of Clostridium botulinum and tetanus bind to gangliosides a s a first step of their toxin activity. Identifying suitable receptors that compete with gangliosides could prevent toxin binding to the neuronal cell s. A possible ganglioside-binding site of the botulinum neurotoxin B (BoNT/ B) has already been proposed and evidence is now presented for a drug bindi ng to botulinum neurotoxin B from structural studies. Doxorubicin, a well k nown DNA intercalator, binds to the neurotoxin at the receptor-binding site proposed earlier. The structure of the BoNT/B-doxorubicin complex reveals that doxorubicin has interactions with the neurotoxin similar to those of s ialyllactose. The aglycone moiety of the doxorubicin stacks with tryptophan 1261 and interacts with histidine 1240 of the binding domain. Here, the po ssibility is presented of designing a potential antagonist for these neurot oxins from crystallographic analysis of the neurotoxin-doxorubicin complex, which will be an excellent lead compound.