nature

当前位置: Nature » 细胞生物学 » 正文

Sci.Rep:同济大学王春光课题组揭示一种芋螺毒素抑制乙酰胆碱受体的全新机制

摘要 : 2015年9月23日,自然出版集团综合性学术期刊《Scientific Reports 》上在线发表了同济大学生命科学学院王春光课题组的题为“Conotoxin αD-GeXXA utilizes a novel strategy to antagonize nicotinic acetylcholine receptors”的研究论文。

 2015年9月23日,自然出版集团综合性学术期刊《Scientific Reports 》上在线发表了同济大学生命科学学院王春光课题组的题为“Conotoxin αD-GeXXA utilizes a novel strategy to antagonize nicotinic acetylcholine receptors”的研究论文。论文由王春光课题组与中科院上海生科院的丁建平教授课题组和澳大利亚RMIT大学David J. Adams教授课题组合作完成,同济大学生命科学学院2010级博士生徐少琼为本文的第一作者。

烟碱型乙酰胆碱受体(nAChR)是乙酰胆碱所介导的神经信号得以传递的关键元件,在神经系统中发挥重要的生物学功能,也与多种疾病密切相关。因此,nAChR也是很多天然毒素的作用靶点。这些毒素不仅促进了对nAChR结构和功能的研究,还可用于相关的药物研发。

芋螺毒素是芋螺分泌的多肽类神经毒素,具有惊人的结构和功能多样性。本研究论文从我国南海的将军芋螺(Conusgeneralis)毒液中发现了一类新型的二聚体毒素αD-GeXXA,能够抑制不同亚型的nAChR。通过αD-GeXXA晶体结构的解析和最小功能结构域的研究,本论文发现αD-GeXXA的单体结构域就具有nAChR的抑制活性,通过结合在nAChR顶部表面来发挥活性;而完整的αD-GeXXA则通过二聚化使其活性得以显著提高。这种结合位点和抑制机制与已知的nAChR抑制方式全然不同,再一次展示了天然毒素中所蕴含的丰富“宝藏”,也为新型nAChR抑制剂的合理设计奠定了理论基础。

原文链接:

Conotoxin αD-GeXXA utilizes a novel strategy to antagonize nicotinic acetylcholine receptors

原文摘要:

Nicotinic acetylcholine receptors (nAChRs) play essential roles in transmitting acetylcholine-mediated neural signals across synapses and neuromuscular junctions, and are also closely linked to various diseases and clinical conditions. Therefore, novel nAChR-specific compounds have great potential for both neuroscience research and clinical applications. Conotoxins, the peptide neurotoxins produced by cone snails, are a rich reservoir of novel ligands that target receptors, ion channels and transporters in the nervous system. From the venom of Conus generalis, we identified a novel dimeric nAChR-inhibiting αD-conotoxin GeXXA. By solving the crystal structure and performing structure-guided dissection of this toxin, we demonstrated that the monomeric C-terminal domain of αD-GeXXA, GeXXA-CTD, retains inhibitory activity against the α9α10 nAChR subtype. Furthermore, we identified that His7 of the rat α10 nAChR subunit determines the species preference of αD-GeXXA, and is probably part of the binding site of this toxin. These results together suggest that αD-GeXXA cooperatively binds to two inter-subunit interfaces on the top surface of nAChR, thus allosterically disturbing the opening of the receptor. The novel antagonistic mechanism of αD-GeXXA via a new binding site on nAChRs provides a valuable basis for the rational design of new nAChR-targeting compounds.

来源: Scientific Reports 浏览次数:0

热门文章TOP

RSS订阅 - 填写您的邮件地址,订阅我们的精彩内容: - 网站地图
网站联系电话:020-87540820 备案号:粤ICP备11050685号-8 增值电信业务经营许可证:粤B2-20120479
©2011-2015 生物帮 All rights reserved.