STRUCTURE AND FUNCTION OF α-BUNGAROTOXIN

Abstract

The long α-neurotoxin, α-Bungarotoxin (Bgtx), from the venom of the Taiwan banded krait, Bungarus multicinctus, is a high affinity competitive antagonist of skeletal muscle-type nicotinic acetylcholine receptors (nAChRs) and of certain homo-oligomeric neuronal nicotinic acetylcholine receptors. Bgtx has a long and illustrious record as a valuable tool for the identification, purification, and localization of skeletal muscle-type nAChRs. The structure and function of Bgtx is of special interest as Bgtx is the prototypical member of a large family of curaremimetic α-neurotoxins from the venoms of Elapidae and Hydrophidae snakes. Bgtx has been the focus of extensive studies aimed at discerning the structural basis for its high affinity interaction with nAChRs. Over the past year, our understanding has advanced significantly with the crystal structure of the acetylcholine-binding protein, AChBP, a nAChR extracellular domain homologue, and with structure determinations of Bgtx and its complexes with receptor-sequence-derived peptide fragments or affinity-selected peptide mimotopes. The heterologous expression of a recombinant Bgtx has facilitated site-directed mutagenesis as an additional approach towards elucidating the structure–function relationship. The results from structural and mutagenesis studies suggest that cation–π interactions play an important role in receptor recognition. Conformational plasticity at the end of the second finger in Bgtx may also be important for specificity and affinity. Finally, a new term, “pharmatope”, is proposed to designate the novel recombinant introduction of Bgtx binding sequences into proteins that are normally unrecognized by Bgtx. Such a “pharmatope” would be an invaluable pharmacological tool allowing experimental access to the multi-purpose derivatives of Bgtx.