LSIII is a neurotoxin found in the venom of the green sea-snake Laticauda semifasciata. It binds tightly and specifically to the nicotinic acetylcholine receptor (AChR), blocking transmission of nerve impulses at the neuromuscular junction and inducing flacid paralysis in prey. The disulfide linkages (shown) are highly conserved among members of the long neurotoxin family. The protruding loop II at the bottom contains many residues shown to contact the acetylcholine receptor. The bridging disulfide in this loop would appear to confer structural regidity, and indeed the NMR structure ensemble hinted at rigid-body motion of the loop relative to the core of the protein via a hinge motion. Subsequent investigation by 13C magnetic relaxation and molecular dynamics simulation confirmed this to be the case. The rigidity of the loop confers an entropic advantage to binding, as fewer degrees of freedom in the neurotoxin are lost on binding. The hinge could provide flexibility that may be necessary to make full contact with the binding site, which evidence suggests lies in a crevice at the iterface of two subunits of AChR. It could also permit the neurotoxin to adapt its conformation in order to remain bound as AChR undergoes binding-induced conformation rearrangement.
Connolly, P. C., Stern, A. S., and Hoch, J. C (1996) Solution structure of LSIII, a long neurotoxin from the venom of Laticauda semifasciata. Biochemistry 35, 418-26.
Connolly, P. C., Stern, A. S., Turner, C. J., and Hoch, J. C (2003) Molecular dynamics of the long neurotoxin. Biochemistry 42, 14443-51.