Variations in “Functional Site” Residues and Classification of Three-Finger Neurotoxins in Snake Venoms

Three-finger toxins (3FTxs) are the largest group of nonenzymatic toxins found in snake venoms. Among them, neurotoxins that target nicotinic acetylcholine receptors are the most well-studied ligands. In addition to the classical neurotoxins, several other new classes have been characterized for their structure, receptor subtype, and species selectivity. Here, we systematically analyzed over 700 amino acid sequences of three-finger neurotoxins that interact with nicotinic acetylcholine receptors. Based on the amino acid residue substitutions in the functional sites and structural features of various classes of neurotoxins, we have classified them into over 150 distinct subgroups. Currently, only a small number of typical examples representing these subgroups have been studied for their structure, function, and subtype selectivity. The functional site residues responsible for their interaction with specific receptor subtypes of several toxins are yet to be identified. The molecular details of each subgroup representative toxin with its target receptor will contribute towards the understanding of subtype- and/or interface-selectivity. Thus, this review will provide new impetus in the toxin research and pave the way for the design of potent, selective ligands for nicotinic acetylcholine receptors.