Three-finger snake neurotoxins and Ly6 proteins targeting nicotinic acetylcholine receptors: pharmacological tools and endogenous modulators

• Lynx1 and its homologs keep the cholinergic system activity at the physiologically appropriate levels.
• Lynx1 has three identified targets: nAChRs, muscarinic acetylcholine receptors, and potassium channels.
• Water-soluble Lynx1 binds competitively at muscle nAChRs, but noncompetitively to neuronal ones.
• Lynx1 and α-neurotoxins appear to differ in their affinity and reversibility of binding to nAChRs.

Snake venom neurotoxins and lymphocyte antigen 6 (Ly6) proteins, most of the latter being membrane tethered by a glycosylphosphatidylinositol (GPI) anchor, have a variety of biological activities, but their three-finger (3F) folding combines them in one Ly6/neurotoxin family. Subsets of two groups, represented by α-neurotoxins and Lynx1, respectively, interact with nicotinic acetylcholine receptors (nAChR) and, hence, are of therapeutic interest for the treatment of neurodegenerative diseases, pain, and cancer. Information on the mechanisms of action and 3D structure of the binding sites, which is required for drug design, is available from the 3D structure of α-neurotoxin complexes with nAChR models. Here, I compare the structural and functional features of α-neurotoxins versus Lynx1 and its homologs to get a clearer picture of Lynx1–nAChR interactions that is necessary for fundamental science and practical applications.