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氯胺酮作用于人NMDA受体的结构基础
2021-07-31 22:05

中国科学院脑科学与智能技术卓越创新中心竺淑佳和中国科学院大学罗成研究组合作取得最新进展。他们揭示了氯胺酮作用于人N-甲基-D-天冬氨酸 (NMDA)受体的结构基础。相关论文发表在2021年7月28日出版的《自然》杂志上。

他们描述了人类 GluN1 – GluN2A 和 GluN1 – GluN2B NMDA 受体与 S-氯胺酮、甘氨酸和谷氨酸复合物的冷冻电镜结构。两个电子密度图都揭示了通道门和选择性过滤器之间中央前庭中 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。两个氨基酸——GluN2A 上的亮氨酸 642(与 GluN2B 上??的亮氨酸 643 同源)和 GluN1 上的天冬酰胺 616——被鉴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。

这些发现从结构上展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。

研究人员表示,氯胺酮是NMDA受体的非竞争性通道阻滞剂。对其他抗抑郁药有抗药性的患者,单次亚麻醉剂量的氯胺酮可产生快速(数小时内)和持久的抗抑郁作用。氯胺酮是 S- 和 R- 氯胺酮对映异构体的外消旋混合物,其中 S- 氯胺酮异构体是活性更强的抗抑郁药。

附:英文原文

Title: Structural basis of ketamine action on human NMDA receptors

Author: Zhang, Youyi, Ye, Fei, Zhang, Tongtong, Lv, Shiyun, Zhou, Liping, Du, Daohai, Lin, He, Guo, Fei, Luo, Cheng, Zhu, Shujia

Issue&Volume: 2021-07-28

Abstract: Ketamine is a non-competitive channel blocker of N-methyl-D-aspartate (NMDA) receptors1. A single sub-anaesthetic dose of ketamine produces rapid (within hours) and long-lasting antidepressant effects in patients who are resistant to other antidepressants2,3. Ketamine is a racemic mixture of S- and R-ketamine enantiomers, with S-ketamine isomer being the more active antidepressant4. Here we describe the cryo-electron microscope structures of human GluN1–GluN2A and GluN1–GluN2B NMDA receptors in complex with S-ketamine, glycine and glutamate. Both electron density maps uncovered the binding pocket for S-ketamine in the central vestibule between the channel gate and selectivity filter. Molecular dynamics simulation showed that S-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.

DOI: 10.1038/s41586-021-03769-9

Source: https://www.nature.com/articles/s41586-021-03769-9

Nature:《自然》,创刊于1869年。隶属于施普林格·自然出版集团,最新IF:43.07
官方网址:http://www.nature.com/
投稿链接:http://www.nature.com/authors/submit_manuscript.html


本期文章:《自然》:Online/在线发表

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