Characterization of a Novel 伪-Conotoxin TxID from Conus textile That Potently Blocks Rat 伪3尾4 Nicotinic Acetylcholine Receptors

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• 作者：Sulan Luo ; Dongting Zhangsun ; Xiaopeng Zhu ; Yong Wu ; Yuanyan Hu ; Sean Christensen ; Peta J. Harvey ; Muharrem Akcan ; David J. Craik ; J. Michael McIntosh
• 刊名：Journal of Medicinal Chemistry
• 出版年：2013
• 出版时间：December 12, 2013
• 年：2013
• 卷：56
• 期：23
• 页码：9655-9663
• 全文大小：490K
• 年卷期：v.56,no.23(December 12, 2013)
• ISSN：1520-4804

文摘

The 伪3尾4 nAChRs are implicated in pain sensation in the PNS and addiction to nicotine in the CNS. We identified an 伪-4/6-conotoxin (CTx) TxID from Conus textile. The new toxin consists of 15 amino acid residues with two disulfide bonds. TxID was synthesized using solid phase methods, and the synthetic peptide was functionally tested on nAChRs heterologously expressed in Xenopus laevis oocytes. TxID blocked rat 伪3尾4 nAChRs with a 12.5 nM IC₅₀, which places it among the most potent 伪3尾4 nAChR antagonists. TxID also blocked the closely related 伪6/伪3尾4 with a 94 nM IC₅₀ but showed little activity on other nAChR subtypes. NMR analysis showed that two major structural isomers exist in solution, one of which adopts a regular 伪-CTx fold but with different surface charge distribution to other 4/6 family members. 伪-CTx TxID is a novel tool with which to probe the structure and function of 伪3尾4 nAChRs.