Natural α-Conotoxins and Their Synthetic Analogues in Study of Nicotinic Acetylcholine Receptors
I. E. Kasheverov , # Yu. N. Utkin , and V. I. Tsetlin
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Shemyakin–Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, ul. Miklukho-Maklaya 16/10, Moscow , 117997 Russia
Received August 29, 2005; in final form, October 25, 2005
Abstract: α-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 α-conotoxins are mainly discussed, taking into consideration the recent results on the ability of α-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 α-conotoxins with AChRs using synthetic analogues of α-conotoxins, mutations in AChRs, and pairwise mutations in both α-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 α-conotoxins also interact. We discuss the interaction of various α-conotoxins with acetylcholine-binding proteins, the recently reported X-ray structure of the complex of the acetylcholine-binding protein from Aplysia californica with the α-conotoxin analogue PnIA, and the application of this structure to the modeling of complexes of α-conotoxins with various AChRs.
Key words: acetylcholine-binding proteins; α-conotoxins, synthetic analogues, structure, biological activity; nicotinic acetylcholine receptors
Russian Journal of Bioorganic Chemistry 2006, 32 (2):103-115