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Structural basis of ketamine action on human NMDA receptors

机译：人NMDA受体对氯胺酮作用的结构基础

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摘要

Ketamine is a non-competitive channel blocker of N-methyl-D-aspartate (NMDA) receptors~(1). A single sub-anaesthetic dose of ketamine produces rapid (within hours) and long-lasting antidepressant effects in patients who are resistant to other antidepressants~(2,3). Ketamine is a racemic mixture of S- and R-ketamine enantiomers, with S-ketamine isomer being the more active antidepressant~(4). 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.
机译：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〜（1）。单一的亚次麻醉剂量的氯胺酮产生快速（在几小时内）和耐药性抗抑郁药的患者的持久抗抑郁作用〜（2,3）。氯胺酮是S-和氯胺酮对映体的外消旋混合物，S-氯胺异构体是更活跃的抗抑郁药〜（4）。在这里，我们用S-氯胺酮，甘氨酸和谷氨酸描述了人物Glun1-Glun2a和Glun1-glun2b NMDA受体的冷冻电子显微镜结构。电子密度图均未在沟道栅极和选择性滤波器之间的中央前程中未覆盖S-氯胺酮的结合口袋。分子动力学模拟显示S-氯胺酮在粘合口袋内的两个不同位置之间移动。 GLUN2A上的两个氨基酸 - 亮氨酸642（对GLUN2B上的亮氨酸643）和GLUN1上的天冬酰胺616 - 鉴定为与氯胺酮形成疏水和氢键相互作用的关键残基，并且这些残基的突变降低了氯胺酮在阻塞中的效力降低了氯胺酮的效力NMDA受体渠道活动。这些发现在结构上显示了氯胺酮的结合和作用于人NMDA受体，并为未来的基于氯胺酮的抗抑郁药的发展铺平道路。

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  • 来源
    《Nature》 |2021年第7871期|301-305|共5页
  • 作者

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

  • 作者单位

    Institute of Neuroscience State Key Laboratory of Neuroscience CAS Center for Excellence in Brain Science and Intelligence Technology Chinese Academy of Sciences|University of Chinese Academy of Sciences;

    College of Life Sciences and Medicine Zhejiang Sci-Tech University;

    Institute of Neuroscience State Key Laboratory of Neuroscience CAS Center for Excellence in Brain Science and Intelligence Technology Chinese Academy of Sciences|University of Chinese Academy of Sciences;

    Institute of Neuroscience State Key Laboratory of Neuroscience CAS Center for Excellence in Brain Science and Intelligence Technology Chinese Academy of Sciences|University of Chinese Academy of Sciences;

    University of Chinese Academy of Sciences|Drug Discovery and Design Center the Center for Chemical Biology State Key Laboratory of Drug Research Shanghai Institute of Materia Medica Chinese Academy of Sciences;

    Drug Discovery and Design Center the Center for Chemical Biology State Key Laboratory of Drug Research Shanghai Institute of Materia Medica Chinese Academy of Sciences;

    Criminal Investigation Technology Department The Third Research Institute of Ministry of Public Security;

    Drug Discovery and Design Center the Center for Chemical Biology State Key Laboratory of Drug Research Shanghai Institute of Materia Medica Chinese Academy of Sciences;

    University of Chinese Academy of Sciences|Drug Discovery and Design Center the Center for Chemical Biology State Key Laboratory of Drug Research Shanghai Institute of Materia Medica Chinese Academy of Sciences;

    Institute of Neuroscience State Key Laboratory of Neuroscience CAS Center for Excellence in Brain Science and Intelligence Technology Chinese Academy of Sciences|University of Chinese Academy of Sciences|Shanghai Center for Brain Science and Brain-Inspired Intelligence Technology;

  • 收录信息 美国《科学引文索引》(SCI);美国《工程索引》(EI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
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