Structural Elucidation of Ivermectin Binding to α7nAChR and the Induced Channel Desensitization.
Structural Elucidation of Ivermectin Binding to α7nAChR and the Induced Channel Desensitization.
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DOI：
10.1021/acschemneuro.2c00783
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发表时间：
2023-03-15
影响因子：
5
通讯作者：
Tang, Pei
中科院分区：
文献类型：
--
作者：
Bondarenko, Vasyl;Chen, Qiang;Singewald, Kevin;Haloi, Nandan;Tillman, Tommy S.;Howard, Rebecca J.;Lindahl, Erik;Xu, Yan;Tang, Pei
α7烟碱乙酰胆碱受体（α7nAChR）介导中枢神经系统和胆碱能抗炎通路中的信号传导。伊维菌素是全长α 7 nAChR的正变构调节剂，也是含有跨膜（TMD）和胞内（ICD）结构域的α 7 nAChR结构的激动剂，但以前尚未确定结合的结构见解。在这里，结合核磁共振作为一个主要的实验工具与Rosetta比较建模和分子动力学模拟，我们揭示了伊维菌素结合的细节α 7 nAChR TMD + ICD和伊维菌素诱导的脱敏状态下相应的结构变化。伊维菌素结合稳定主要是通过疏水相互作用，从邻近亚基之间的界面残基附近的TMD的细胞外端，其中亚基间的差距大幅扩大相比，载脂蛋白结构。离子渗透途径显示出明显不同于静息态的曲线，但与脱敏α7nAChR的曲线相似。ICD还表现出结构变化，包括MX和H3螺旋相对于通道轴的重新取向。与伊维菌素复合的α 7 nAChR TMD + ICD的所得结构为发现治疗潜力的新调节剂和探索不同α 7 nAChR功能状态下细胞质信号传导的结构基础提供了机会。
The α7 nicotinic acetylcholine receptor (α7nAChR) mediates signaling in the central nervous system and cholinergic anti-inflammatory pathways. Ivermectin is a positive allosteric modulator of a full-length α7nAChR and an agonist of the α7nAChR construct containing transmembrane (TMD) and intracellular (ICD) domains, but structural insights of the binding have not previously been determined. Here, combining nuclear magnetic resonance as a primary experimental tool with Rosetta comparative modeling and molecular dynamics simulations, we have revealed details of ivermectin binding to the α7nAChR TMD + ICD and corresponding structural changes in an ivermectin-induced desensitized state. Ivermectin binding was stabilized predominantly by hydrophobic interactions from interfacial residues between adjacent subunits near the extracellular end of the TMD, where the inter-subunit gap was substantially expanded in comparison to the apo structure. The ion-permeation pathway showed a profile distinctly different from the resting-state profile but similar to profiles of desensitized α7nAChR. The ICD also exhibited structural changes, including reorientation of the MX and h3 helices relative to the channel axis. The resulting structures of the α7nAChR TMD + ICD in complex with ivermectin provide opportunities for discovering new modulators of therapeutic potential and exploring the structural basis of cytoplasmic signaling under different α7nAChR functional states.
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人α7烟碱乙酰胆碱受体的高度柔性细胞内结构域的结构。
影响因子：
16.6
作者：
Bondarenko V;Wells MM;Chen Q;Tillman TS;Singewald K;Lawless MJ;Caporoso J;Brandon N;Coleman JA;Saxena S;Lindahl E;Xu Y;Tang P
通讯作者：
Tang P
影响因子：
5
作者：
Honorato RV;Koukos PI;Jiménez-García B;Tsaregorodtsev A;Verlato M;Giachetti A;Rosato A;Bonvin AMJJ
通讯作者：
Bonvin AMJJ
影响因子：
4.8
作者：
Feduccia AA;Chatterjee S;Bartlett SE
通讯作者：
Bartlett SE
影响因子：
3.3
作者：
Cheng, Mary H.;Xu, Yan;Tang, Pei
通讯作者：
Tang, Pei
DOI：
10.1007/s11481-015-9601-5
发表时间：
2015-09
期刊：
Journal of neuroimmune pharmacology : the official journal of the Society on NeuroImmune Pharmacology
影响因子：
--
作者：
Báez-Pagán CA;Delgado-Vélez M;Lasalde-Dominicci JA
通讯作者：
Lasalde-Dominicci JA