Druggability Simulations and X-Ray Crystallography Reveal a Ligand-Binding Site in the GluA3 AMPA Receptor N-Terminal Domain.
Druggability Simulations and X-Ray Crystallography Reveal a Ligand-Binding Site in the GluA3 AMPA Receptor N-Terminal Domain.
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DOI：
10.1016/j.str.2018.10.017
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发表时间：
2019-02
期刊：
影响因子：
5.7
通讯作者：
J. Lee;James M. Krieger;B. Herguedas;J. García-Nafría;Anindita Dutta;S. Shaikh;I. Greger;I. Bahar-I.
中科院分区：
文献类型：
--
作者：
J. Lee;James M. Krieger;B. Herguedas;J. García-Nafría;Anindita Dutta;S. Shaikh;I. Greger;I. Bahar-I.
离子型谷氨酸受体 (iGluR) 介导大脑中的大部分兴奋性神经传递。它们的功能障碍与许多神经系统疾病有关，使 iGluRs 成为潜在的药物靶点。在这里，我们在类药物分子存在的情况下使用分子动力学模拟，对两个主要 iGluR 亚家族的成药性进行了系统分析。我们通过忠实识别 AMPA 受体 (AMPAR) 和 NMDA 受体上已知的激动剂和调节剂位点，证明了成药性模拟的适用性。模拟产生了 AMPAR 配体结合域响应激动剂的预期变构变化。我们还发现了一个特异于 GluA3 AMPAR N 端结构域 (NTD) 的新型配体结合位点，这是由于其独特的构象灵活性，我们进一步探索了处于截然不同状态的晶体结构。除了对 iGluR NTD 动力学进行深入分析外，我们的方法还可以识别可药物位点并允许确定新型 iGluR 调节剂的药效特征。
Ionotropic glutamate receptors (iGluRs) mediate the majority of excitatory neurotransmission in the brain. Their dysfunction is implicated in many neurological disorders, rendering iGluRs potential drug targets. Here, we performed a systematic analysis of the druggability of two major iGluR subfamilies, using molecular dynamics simulations in the presence of drug-like molecules. We demonstrate the applicability of druggability simulations by faithfully identifying known agonist and modulator sites on AMPA receptors (AMPARs) and NMDA receptors. Simulations produced the expected allosteric changes of the AMPAR ligand-binding domain in response to agonist. We also identified a novel ligand-binding site specific to the GluA3 AMPAR N-terminal domain (NTD), resulting from its unique conformational flexibility that we explored further with crystal structures trapped in vastly different states. In addition to providing an in-depth analysis into iGluR NTD dynamics, our approach identifies druggable sites and permits the determination of pharmacophoric features toward novel iGluR modulators.