Structural and Functional Characterization of a Novel α-Conotoxin Mr1.7 from Conus marmoreus Targeting Neuronal nAChR α3β2, α9α10 and α6/α3β2β3 Subtypes.
Structural and Functional Characterization of a Novel α-Conotoxin Mr1.7 from Conus marmoreus Targeting Neuronal nAChR α3β2, α9α10 and α6/α3β2β3 Subtypes.
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DOI：
10.3390/md13063259
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发表时间：
2015-05-27
期刊：
影响因子：
5.4
通讯作者：
Dai Q
中科院分区：
文献类型：
--
作者：
Wang S;Zhao C;Liu Z;Wang X;Liu N;Du W;Dai Q
在本研究中，我们合成了一种新的α4/7-松果毒素Mr1.7 (PECCTHPACHVSHPELC-NH2)，并对其进行了结构和功能鉴定。核磁共振溶液结构表明，Mr1.7含有从Pro7到His10的310-螺旋结构和从Pro14到Cys17的I型β-旋转。电生理结果显示，Mr1.7选择性抑制α3β2、α9α10和α6/α3β2β3神经元烟碱乙酰胆碱受体（nAChR）， IC50分别为53.1 nM、185.7 nM和284.2 nM，但对其他nAChR亚型无抑制作用。进一步对Mr1.7的结构活性研究表明，Mr1.7 n端序列的PE残基对其选择性的调节很重要，而用Ala取代Glu2导致Mr1.7对α3β2 nAChR的效价和选择性显著提高。此外，用环2中的Asn取代Ser12显著增加Mr1.7与α3β2、α3β4、α2β4和α7 nAChR亚型的结合。总之，这项工作扩大了我们对选择性的认识，并提供了一种新的方法来提高nAChR亚型抑制剂的效力和选择性。
In the present study, we synthesized and, structurally and functionally characterized a novel α4/7-conotoxin Mr1.7 (PECCTHPACHVSHPELC-NH2), which was previously identified by cDNA libraries from Conus marmoreus in our lab. The NMR solution structure showed that Mr1.7 contained a 310-helix from residues Pro7 to His10 and a type I β-turn from residues Pro14 to Cys17. Electrophysiological results showed that Mr1.7 selectively inhibited the α3β2, α9α10 and α6/α3β2β3 neuronal nicotinic acetylcholine receptors (nAChRs) with an IC50 of 53.1 nM, 185.7 nM and 284.2 nM, respectively, but showed no inhibitory activity on other nAChR subtypes. Further structure-activity studies of Mr1.7 demonstrated that the PE residues at the N-terminal sequence of Mr1.7 were important for modulating its selectivity, and the replacement of Glu2 by Ala resulted in a significant increase in potency and selectivity to the α3β2 nAChR. Furthermore, the substitution of Ser12 with Asn in the loop2 significantly increased the binding of Mr1.7 to α3β2, α3β4, α2β4 and α7 nAChR subtypes. Taken together, this work expanded our knowledge of selectivity and provided a new way to improve the potency and selectivity of inhibitors for nAChR subtypes.
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