page_title: Three-finger toxin
section_title: Structure-function activity relationships
hierarchical_section_title: Three-finger toxin / Function / Structure-function activity relationships
caption_attribution_description: English: The complex formed by alpha-bungarotoxin (blue) bound to the extracellular domain of the alpha-9 nicotinic acetylcholine receptor (nAChR, orange). The toxin is a long-chain three-finger toxin whose interactions with the receptor are mediated through loops I and II. Disulfide bonds - four conserved bonds in the toxin core and one in loop II - are shown in yellow. Rendered from PDB ID 4UY2. Crystal Structures of Free and Antagonist-Bound States of Human Alpha9 Nicotinic Receptor Extracellular Domain. Zouridakis, M., Giastas, P., Zarkadas, E., Chroni-Tzartou, D., Bregestovski, P., Tzartos, S.J. (2014) Nat.Struct.Mol.Biol. 21: 976 PMID: 25282151 DOI: 10.1038/nsmb.2900
context_page_description: Three-finger toxins are a protein superfamily of small toxin proteins found in the venom of snakes. Three-finger toxins are in turn members of a larger superfamily of three-finger protein domains which includes non-toxic proteins that share a similar protein fold. The group is named for its common structure consisting of three beta strand loops connected to a central core containing four conserved disulfide bonds. The 3FP protein domain has no enzymatic activity and is typically between 60-74 amino acid residues long. Despite their conserved structure, three-finger toxin proteins have a wide range of pharmacological effects. Most members of the family are neurotoxins that act on cholinergic intercellular signaling; the alpha-neurotoxin family interacts with muscle nicotinic acetylcholine receptors, the kappa-bungarotoxin family with neuronal nAChRs, and muscarinic toxins with muscarinic acetylcholine receptors.
context_section_description: Because 3FTx proteins of similar structure bind a diverse range of cellular protein targets, the relationships between 3FTx protein sequence and their biological activity have been studied extensively, especially among the alpha-neurotoxins. Known functional sites conferring binding affinity and specificity are concentrated in the loops of 3FTx proteins. For example, the crystal structure of alpha-bungarotoxin in complex with the extracellular domain of the alpha-9 nAChR subunit indicates a protein-protein interaction mediated through loops I and II, with no contacts formed by loop III. Interaction surfaces have been mapped for a number of toxins and vary in which loops participate in binding; erabutoxin A uses all three loops to bind nAChRs, while the dendroaspin interaction with adhesion proteins is mediated by three residues in loop III. In some 3FTx proteins with a C-terminal extension, these residues also participate in forming key binding interactions.
  The cardiotoxin/cytolysin 3FTx subgroup has a somewhat different set of functionally significant residues due to its distinct mechanism of action, likely involving interactions with phospholipids in the cell membrane, as well as possible functionally significant interactions with other cell-surface molecules such as glycosaminoglycans. A hydrophobic patch of residues contiguous in tertiary structure but distributed over all three loops has been identified as functionally significant in combination with a set of conserved lysine residues conferring local positive charge.
  Because of their structural similarity and functional diversity, 3FTx proteins have been used as model systems for the study of protein engineering. Their high binding specificity against targets of pharmacological interest, lack of enzymatic activity, and low immunogenicity have also prompted interest in their potential as drug leads.
caption: Structure of alpha-bungarotoxin (blue) in complex with the alpha-9 nAChR subunit (orange), showing interactions with loops I and II.[18]
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