Yelshanskaya Maria V, Singh Appu K, Sampson Jared M, Narangoda Chamali, Kurnikova Maria, Sobolevsky Alexander I
Department of Biochemistry and Molecular Biophysics, Columbia University, 650 West 168(th) Street, New York, NY 10032, USA.
Chemistry Department, Carnegie Mellon University, 4400 Fifth Avenue, Pittsburgh, PA 15213, USA.
Neuron. 2016 Sep 21;91(6):1305-1315. doi: 10.1016/j.neuron.2016.08.012. Epub 2016 Sep 8.
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.
兴奋性神经传递在癫痫发生过程中起关键作用。相应地，介导大部分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前景靶点。最有效且耐受性良好的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良副作用。对非竞争性抑制缺乏结构上的理解阻碍了更好药物的设计。在此，我们报告了大鼠AMPA亚型GluA2受体与三种非竞争性抑制剂复合物的晶体结构。这些抑制剂结合到一个在大鼠和人类之间完全保守的新结合位点，该位点位于离子通道与将其连接到配体结合域的连接子之间的界面处。我们提出，这些抑制剂通过在跨膜片段之间充当楔子来稳定AMPA受体的关闭状态，从而防止离子通道开放所必需的门控重排。
