Structural basis of ketamine action on human NMDA receptors

Youyi Zhang, Fei Ye, Tongtong Zhang, Shiyun Lv, Liping Zhou, Daohai Du, He Lin, Fei Guo, Cheng Luo () and Shujia Zhu ()
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Youyi Zhang: CAS Center for Excellence in Brain Science and Intelligence Technology, Chinese Academy of Sciences
Fei Ye: Zhejiang Sci-Tech University
Tongtong Zhang: CAS Center for Excellence in Brain Science and Intelligence Technology, Chinese Academy of Sciences
Shiyun Lv: CAS Center for Excellence in Brain Science and Intelligence Technology, Chinese Academy of Sciences
Liping Zhou: University of Chinese Academy of Sciences
Daohai Du: State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences
He Lin: The Third Research Institute of Ministry of Public Security
Fei Guo: State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences
Cheng Luo: University of Chinese Academy of Sciences
Shujia Zhu: CAS Center for Excellence in Brain Science and Intelligence Technology, Chinese Academy of Sciences

Nature, 2021, vol. 596, issue 7871, 301-305

Abstract: 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 containing equal parts of (R)- and (S)-ketamine, with the (S)-enantiomer having greater affinity for the NMDA receptor4. 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.

Date: 2021
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DOI: 10.1038/s41586-021-03769-9

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