Structural basis of ketamine action on human NMDA receptors
Structural basis of ketamine action on human NMDA receptors
复制标题
氯胺酮对人 NMDA 受体作用的结构基础
DOI：
10.1038/s41586-021-03769-9
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发表时间：
2021-07-28
期刊：
影响因子：
64.8
通讯作者：
Zhu, Shujia
中科院分区：
文献类型：
--
作者：
Zhang, Youyi;Ye, Fei;Zhu, Shujia
氯胺酮是N-甲基-D-天冬氨酸（NMDA）受体的非竞争性通道阻滞剂。单次亚麻醉剂量的氯胺酮在对其他抗抑郁药耐药的患者中产生快速（数小时内）和持久的抗抑郁作用。氯胺酮是一种外消旋混合物，含有等份的（R）-和（S）-氯胺酮，（S）-对映体对NMDA受体具有更大的亲和力。在这里，我们描述了冷冻电子显微镜结构的人GluN 1-GluN 2A和GluN 1-GluN 2B NMDA受体的复合物与S-氯胺酮，甘氨酸和谷氨酸。两个电子密度图均揭示了通道门和选择性过滤器之间的中央前庭中S-氯胺酮的结合口袋。分子动力学模拟表明S-氯胺酮在结合口袋内的两个不同位置之间移动。GluN 2A上的亮氨酸642（与GluN 2B上的亮氨酸643同源）和GluN 1上的天冬酰胺616被确定为与氯胺酮形成疏水和氢键相互作用的关键残基，这些残基的突变降低了氯胺酮阻断NMDA受体通道活性的效力。这些发现在结构上显示了氯胺酮如何结合并作用于人类NMDA受体，并为未来开发基于氯胺酮的抗抑郁药铺平了道路。
Ketamine is a non-competitive channel blocker ofN-methyl-d-aspartate (NMDA) receptors. A single sub-anaesthetic dose of ketamine produces rapid (within hours) and long-lasting antidepressant effects in patients who are resistant to other antidepressants,. Ketamine is a racemic mixture containing equal parts of (R)- and (S)-ketamine, with the (S)-enantiomer having greater affinity for the NMDA receptor. Here we describe the cryo-electron microscope structures of human GluN1–GluN2A and GluN1–GluN2B NMDA receptors in complex withS-ketamine, glycine and glutamate. Both electron density maps uncovered the binding pocket forS-ketamine in the central vestibule between the channel gate and selectivity filter. Molecular dynamics simulation showed thatS-ketamine moves between two distinct locations within the binding pocket. Two amino acids—leucine 642 on GluN2A (homologous to leucine 643 on GluN2B) and asparagine 616 on GluN1—were identified as key residues that form hydrophobic and hydrogen-bond interactions with ketamine, and mutations at these residues reduced the potency of ketamine in blocking NMDA receptor channel activity. These findings show structurally how ketamine binds to and acts on human NMDA receptors, and pave the way for the future development of ketamine-based antidepressants.