Kasheverov I E, Utkin Iu N, Tsetlin V I
Bioorg Khim. 2006 Mar-Apr;32(2):115-29. doi: 10.1134/s1068162006020014.
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.
本文综述了α-芋螺毒素，这是一种从芋螺属有毒海洋蜗牛中提取的肽类神经毒素，能高度特异性地阻断各种类型的烟碱型乙酰胆碱受体（AChRs）。首先，简要讨论了肌肉型和神经型AChRs的结构组织、它们在生理过程中的作用以及在各种疾病中的角色。在此背景下，论证了使用神经毒素和其他方法对AChR亚型进行定量测定的必要性。主要讨论了α-芋螺毒素的化学结构、空间组织和特异性，同时考虑到α-芋螺毒素与具有高度物种特异性的肌肉或神经异源和同源寡聚AChRs相互作用的最新研究结果。特别强调了利用α-芋螺毒素的合成类似物、AChRs中的突变以及α-芋螺毒素和AChRs中的成对突变，对α-芋螺毒素与AChRs相互作用表面进行全面表征。2001年从椎实螺中发现乙酰胆碱结合蛋白并确定其晶体结构，这使得在理解α-芋螺毒素也能与之相互作用的AChRs配体结合结构域的结构组织方面取得了快速进展。我们讨论了各种α-芋螺毒素与乙酰胆碱结合蛋白的相互作用、最近报道的加州海兔乙酰胆碱结合蛋白与α-芋螺毒素类似物PnIA复合物的X射线结构，以及该结构在α-芋螺毒素与各种AChRs复合物建模中的应用。
