Botulinum Neurotoxins

Clostridial neurotoxins are responsible for disrupting neurotransmission. They include tetanus toxin and the 7 serotypes of botulinum toxin. We are determining the molecular events involved in the binding, pore formation, translocation, and catalysis of botulinum neurotoxin. Although botulinum toxin is most known for its deadly effects, it is now being used therapeutically to treat involuntary muscle disorders such as cerebral palsy and neuromuscular dystonias. Previously, we determined the structures of the 150-kD holotoxin form, the holotoxin bound to antibodies, and the catalytic domains of several serotypes (A, B, D, F, G). Recently, we determined the structure of the cell-surface receptor toxin complex (see Figure on the left). These structures are being used to understand and redesign the toxin's mechanism of action and to determine additional therapeutic applications of the toxin.

Figure. A. Model of binding of type B botulinum neurotoxin via both Syt-II and ganglioside receptors at the presynaptic membrane. The cytoplasm domain of synaptotagmin is presented as 2 C2 domains (light pink) bound with calcium ions (yellow spheres), modeled by 1TJX and 1DQV. Reprinted from Chai, Q., Arndt, J.W., Dong, M., Tepp, W.H., Johnson, E.A., Chapman, E.R., Stevens, R.C. Structural basis of cell surface receptor recognition by botulinum neurotoxin B. Nature 444:1096, 2006.
B. Overview of type A1 botulinum neurotoxin (yellow) in complex with the CR1 antibody (antibody heavy and light chains in magenta and green, respectively). Reprinted from Garcia-Rodriguez, C., Levy, R., Arndt, J.W., Forsyth, C.M., Razai, A., Lou, J., Geren, I., Stevens, R.C., Marks, J.D. Molecular evolution of antibody cross-reactivity for two subtypes of type A botulinum neurotoxin. Nat. Biotechnol. 25:107, 2007.