Three-Finger α-Neurotoxins and the Nicotinic Acetylcholine Receptor, Forty Years On

Abstract

Abstract. The discovery, about forty years ago, of a -bungarotoxin, a three-finger a -neurotoxin from Bungarus multicinctus venom, enabled the isolation of the nicotinic acetylcholine receptor (nAChR), making it one of the most thoroughly characterized receptors today. Since then, the sites of interaction between a -neurotoxins and nAChRs have largely been delineated, revealing the remarkable plasticity of the three-finger toxin fold that has optimally evolved to utilize different combinations of functional groups to generate a panoply of target specificities to discern subtle differences between nAChR subtypes. New facets in toxinology have now broadened the scope for the use of a-neurotoxins in scientific discovery. For instance, the development of short, combinatorial library-derived, synthetic peptides that bind with subnanomolar affinity to a -bungarotoxin and prevent its interaction with muscle nAChRs has led to the in vivo neutralization of experimental a -bungarotoxin envenomation, while the successful introduction of pharmatopes bearing "a -bungarotoxin-sensitive sites" into toxin-insensitive nAChRs has permitted the use of various a -neurotoxin tags to localize and characterize new receptor subtypes. More ambitious strategies can now be envisaged for engineering rationally designed novel activities on three-finger toxin scaffolds to generate lead peptides of therapeutic value that target the nicotinic pharmacopoeia. This review details the progress made towards achieving this goal.

Lachesis muta (Viperidae) cDNAs Reveal Diverging Pit Viper Molecules and Scaffolds Typical of Cobra (Elapidae) Venoms: Implications for Snake Toxin Repertoire Evolution

“…These are short proteins, 60-75 residues long, involved in several pharmacological effects, which are most related to their ability to bind and block nicotinic acetylcholine receptors, resulting in the famous postsynaptic neurotoxicity of oriental and marine snake venoms (Nirthanan and Gwee 2004). Different from the above case of ohanin-like toxin, which is a recently described class of toxin, during the last 50 years there have been up to 350 sequences of snake 3FTx found exclusively in Elapidae (including Hydrophiinae) venoms and only recently in Colubridae (Fry et al 2003a).…”

“…The most important conserved feature of their sequences is the cysteine arrangement, which involves four or five disulfide bonds responsible for the characteristic structure of three b-sheet looped domains, known as the ''three-finger'' shape. The distinctive features of their sequences have been largely correlated to the particular activities, making these short toxins a good target for structure-function and drug development studies (Menez 1998;Nirthanan and Gwee 2004). This shape also appears in some other groups of proteins, as follows (see Figure 6A): (i) as the whole molecule of some secreted proteins, such as the frog toxin xenoxin and the mammal blood protein SLURP1; (ii) as part of physiological surface proteins containing a hydrophobic GPI consensus at the C terminus, such as CD59 antigen, Ly6, and Lynx; (iii) as the N-terminal half of the snake plasma gamma PLA2 inhibitor (gPLI); and (iv) three times in tandem repeated in the urokinase plasminogen activator receptor (uPAR).…”

Structural and Functional Characterization of a Novel Homodimeric Three-finger Neurotoxin from the Venom of Ophiophagus hannah (King Cobra)

“…Depending on the target receptors, these neurotoxins can be broadly divided into various groups. Curaremimetic or ␣-neurotoxins that target muscle (␣␤␥␦ or ␣ 1 subtype) nAChRs (7,16,23) belong to short-chain and long-chain neurotoxins (classified based on size and number of disulfide bridges (24)). Long-chain neurotoxins, but not short-chain neurotoxins, also target neuronal ␣ 7 -nAChRs associated with neurotransmission in the brain (25).…”

PATE Gene Clusters Code for Multiple, Secreted TFP/Ly-6/uPAR Proteins That Are Expressed in Reproductive and Neuron-rich Tissues and Possess Neuromodulatory Activity

“…The diversity of nAChRs engendered by the combinatorial assembly of various nicotinic subunits (␣1-␣10, ␤1-␤4, ␦, ␥, and ⑀) indicates different electrical and binding properties for each combinatorial subtype (28). One would thus naturally expect that modulations of their activity would necessitate a diversity of interacting modulators.…”