The crystal structure of a post-synaptic neurotoxin from sea snake at 2.2 Å resolution

Abstract

Among the most lethal proteins in the venoms of sea snakes and elapid land snakes are the post-synaptic neurotoxins. These act by blocking the nicotinic acetylcholine receptor of the muscle motor end plate [ 1 ] , thus preventing transmission across the cholinergic synapse. Because of their extremely specific and tight binding to the receptor (KD is on the order of lo-“), these toxins have been the object of intensive chemical study [2], and have also been used to isolate the receptor protein [3,4] . Up to now there has been no information on the three-dimensional structure of the neurotoxins to aid in understanding their mode of action. We have solved the crystal structure of a neurotoxin from the sea snake Laticauda semifasciata from the Philippines Sea. This is a ‘short’ neurotoxin of 62 amino acids cross-linked by four disulfide bridges [S] . The structure has been determined at 2.2 A resolution. The molecule is a disc with one extended loop containing most of the residues believed essential for toxicity. We conclude that this structure is common to all snake venom neurotoxins, and that the postsynaptic toxins act by inserting the loop into a cleft or channel in the acetylcholine receptor.