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首页> 外文期刊>Neuron >Structural Bases of Noncompetitive Inhibition of AMPA-Subtype Ionotropic Glutamate Receptors by Antiepileptic Drugs
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Structural Bases of Noncompetitive Inhibition of AMPA-Subtype Ionotropic Glutamate Receptors by Antiepileptic Drugs

机译：抗癫痫药非竞争性抑制AMPA亚型离子型谷氨酸受体的结构基础

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摘要

Excitatory neurotransmission plays a key role in epileptogenesis. Correspondingly, AMPA-subtype ionotropic glutamate receptors, which mediate the majority of excitatory neurotransmission and contribute to seizure generation and spread, have emerged as promising targets for epilepsy therapy. The most potent and well-tolerated AMPA receptor inhibitors act via a noncompetitive mechanism, but many of them produce adverse side effects. The design of better drugs is hampered by the lack of a structural understanding of noncompetitive inhibition. Here, we report crystal structures of the rat AMPA-subtype GluA2 receptor in complex with three noncompetitive inhibitors. The inhibitors bind to a novel binding site, completely conserved between rat and human, at the interface between the ion channel and linkers connecting it to the ligand-binding domains. We propose that the inhibitors stabilize the AMPA receptor closed state by acting as wedges between the transmembrane segments, thereby preventing gating rearrangements that are necessary for ion channel opening.
机译：兴奋性神经传递在癫痫发生中起关键作用。相应地，介导大多数兴奋性神经传递并促成癫痫发作和扩散的AMPA亚型离子型谷氨酸受体已成为癫痫治疗的有希望的靶标。最有效和耐受性最强的AMPA受体抑制剂通过非竞争性机制起作用，但其中许多会产生不利的副作用。缺乏对非竞争性抑制的结构性理解阻碍了更好药物的设计。在这里，我们报告与三种非竞争性抑制剂复合的大鼠AMPA亚型GluA2受体的晶体结构。抑制剂在离子通道和将其连接至配体结合域的接头之间的界面处结合至在大鼠和人之间完全保守的新结合位点。我们建议抑制剂通过充当跨膜片段之间的楔形物来稳定AMPA受体的闭合状态，从而防止离子通道打开所需的门控重排。

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