伊维菌素与 α7nAChR 结合的结构解析和诱导的通道脱敏,ACS Chemical Neuroscience

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伊维菌素与 α7nAChR 结合的结构解析和诱导的通道脱敏
ACS Chemical Neuroscience ( IF 4.1 ) Pub Date : 2023-02-23 , DOI: 10.1021/acschemneuro.2c00783
Vasyl Bondarenko ₁ , Qiang Chen ₁ , Kevin Singewald ₂ , Nandan Haloi _{3,

4} , Tommy S Tillman ₁ , Rebecca J Howard _{3,

4} , Erik Lindahl _{3,

4} , Yan Xu _{1,

5,

6,

7} , Pei Tang _{1,

5,

8}

Affiliation

α7 烟碱型乙酰胆碱受体 (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 α7nAChR 的正变构调节剂和包含跨膜 (TMD) 和细胞内 (ICD) 结构域的 α7nAChR 构建体的激动剂，但之前尚未确定结合的结构见解。在这里，将核磁共振作为主要实验工具与 Rosetta 比较建模和分子动力学模拟相结合，我们揭示了伊维菌素与 α7nAChR TMD + ICD 结合的细节以及伊维菌素诱导的脱敏状态下的相应结构变化。伊维菌素的结合主要通过 TMD 细胞外端附近相邻亚基之间的界面残基的疏水相互作用来稳定，与 apo 结构相比，亚基间间隙显着扩大。离子渗透途径显示出明显不同于静息态分布但类似于脱敏 α7nAChR 分布的分布。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定向。α7nAChR TMD + ICD 与伊维菌素复合物的所得结构为发现具有治疗潜力的新调节剂和探索不同 α7nAChR 功能状态下细胞质信号传导的结构基础提供了机会。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定向。α7nAChR TMD + ICD 与伊维菌素复合物的所得结构为发现具有治疗潜力的新调节剂和探索不同 α7nAChR 功能状态下细胞质信号传导的结构基础提供了机会。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定向。α7nAChR TMD + ICD 与伊维菌素复合物的所得结构为发现具有治疗潜力的新调节剂和探索不同 α7nAChR 功能状态下细胞质信号传导的结构基础提供了机会。

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Structural Elucidation of Ivermectin Binding to α7nAChR and the Induced Channel Desensitization

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.

更新日期：2023-02-23

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