[Natural alpha-conotoxins and their synthetic analogues in studies of nicotinic acetylcholine receptors].
alpha-Conotoxins, peptide neurotoxins from poisonous marine snails of the genus Conus that highly specifically block nicotinic acetylcholine receptors (AChRs) of various types, are reviewed. Preliminarily, the structural organization of AChRs of the muscular and neuronal types, their involvement in physiological processes, and their role in various diseases are briefly discussed. In this connection, the necessity of quantitative determination of AChR subtypes using neurotoxins and other approaches is substantiated. The chemical structure, spatial organization, and specificity of alpha-conotoxins are mainly discussed, taking into consideration the recent results on the ability of alpha-conotoxins to interact with muscular or neuronal hetero- and homooligomeric AChRs exhibiting a high species specificity. Particular emphasis is placed upon a thorough characterization of the surfaces of interaction of alpha-conotoxins with AChRs using synthetic analogues of alpha-conotoxins, mutations in AChRs, and pairwise mutations in both alpha-conotoxins and AChRs. The discovery in 2001 of the acetylcholine-binding protein from the pond snail Lymnaea stagnalis and the determination of its crystalline structure led to rapid progress in understanding the structural organization of ligand-binding domains of AChRs with which alpha-conotoxins also interact. We discuss the interaction of various alpha-conotoxins with acetylcholine-binding proteins, the recently reported X-ray structure of the complex of the acetylcholine-binding protein from Aplysia californica with the alpha-conotoxin analogue PnIA, and the application of this structure to the modeling of complexes of alpha-conotoxins with various AChRs.
Kasheverov
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Utkin
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Tsetlin
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D000818:Animals; D020916:Conotoxins / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D052078:Conus Snail / Q000737:chemistry*; D008024:Ligands; D008958:Models, Molecular; D009154:Mutation; D009498:Neurotoxins / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D018733:Nicotinic Antagonists / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology; D011487:Protein Conformation; D011978:Receptors, Nicotinic / Q000187:drug effects* / Q000378:metabolism
D020916:Conotoxins; D008024:Ligands; D009498:Neurotoxins; D018733:Nicotinic Antagonists; D011978:Receptors, Nicotinic; C089038:alpha-conotoxin PnIA