Abstract
Nicotinic acetylcholine receptors (nAChRs) fulfill a variety of functions making identification and analysis of nAChR subtypes a challenging task. Traditional instruments for nAChR research are d-tubocurarine, snake venom protein α-bungarotoxin (α-Bgt), and α-conotoxins, neurotoxic peptides from Conus snails. Various new compounds of different structural classes also interacting with nAChRs have been recently identified. Among the low-molecular weight compounds are alkaloids pibocin, varacin and makaluvamines C and G. 6-Bromohypaphorine from the mollusk Hermissenda crassicornis does not bind to Torpedo nAChR but behaves as an agonist on human α7 nAChR. To get more selective α-conotoxins, computer modeling of their complexes with acetylcholine-binding proteins and distinct nAChRs was used. Several novel three-finger neurotoxins targeting nAChRs were described and α-Bgt inhibition of GABA-A receptors was discovered. Information on the mechanisms of nAChR interactions with the three-finger proteins of the Ly6 family was found. Snake venom phospholipases A2 were recently found to inhibit different nAChR subtypes. Blocking of nAChRs in Lymnaea stagnalis neurons was shown for venom C-type lectin-like proteins, appearing to be the largest molecules capable to interact with the receptor. A huge nAChR molecule sensible to conformational rearrangements accommodates diverse binding sites recognizable by structurally very different compounds.
Highlights
Nicotinic acetylcholine receptors have been in the focus of researchers interested in fundamental problems of neurobiology, pharmacology and drug design for several decades
Very rich information is compiled about the three-dimensional organization, topography of binding sites and mechanisms of action for the Nicotinic acetylcholine receptors (nAChRs) major types based on the Torpedo receptor 3D structure, computer modeling and the X-ray structures of the acetylcholine-binding proteins (AChBPs) [9,10], which are excellent models of the ligand-binding domains of all nAChRs
Even more interesting are the AChBP crystalline complexes with various cholinergic agonists: carbamylcholine and nicotine [11], epibatidine [12,13], as well as with antagonists: d-tubocurarine [14], snake venom α-neurotoxins [15,16], and α-conotoxins from Conus marine snails [10,17,18]
Summary
Nicotinic acetylcholine receptors (nAChRs) have been in the focus of researchers interested in fundamental problems of neurobiology, pharmacology and drug design for several decades. Very rich information is compiled about the three-dimensional organization, topography of binding sites and mechanisms of action for the nAChR major types based on the Torpedo receptor 3D structure, computer modeling and the X-ray structures of the acetylcholine-binding proteins (AChBPs) [9,10], which are excellent models of the ligand-binding domains of all nAChRs. Even more interesting are the AChBP crystalline complexes with various cholinergic agonists: carbamylcholine and nicotine [11], epibatidine [12,13], as well as with antagonists: d-tubocurarine [14], snake venom α-neurotoxins [15,16], and α-conotoxins from Conus marine snails [10,17,18]. To briefly consider new results on low molecular compounds from natural sources as well as on peptide and protein neurotoxins, focusing on our recent results in this field
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