Chinese Academy of Sciences "Nature" reveals the molecular mechanism of the antidepressant ketamine targeting human NMDA receptors

At 23:00 on July 28, 2021, the journal Nature published an online research paper titled "Structural basis of ketamine acting on human NMDA receptors".

Depression affects more than 300 million people worldwide, and nearly 800,000 depressed patients commit suicide every year

Existing studies have shown that ketamine, as an important glutamate-gated ion channel NMDA receptor blocker in the brain, can participate in the regulation of synaptic transmission and synaptic plasticity signaling pathways by inhibiting the activity of NMDA receptor channels.

In this study, Zhu Shujia’s team first used cryo-electron microscopy to analyze the three-dimensional structure of ketamine-bound human GluN1-GluN2A and GluN1-GluN2B subtypes of NMDA receptors.

In order to further analyze the interaction between the receptor and ketamine, Luo Cheng’s team analyzed the dynamic changes of ketamine in the cavity through molecular dynamics simulations, and found that there are "upper" and "lower" in the cavity of ketamine.

This study "sees" and confirms the binding site of ketamine on the NMDA receptor through electron microscopy, and combined with molecular dynamics simulations to reveal the hydrogen bonding effect of GluN1-N616 and the hydrophobic effect of GluN2A-L642 in the stable binding of ketamine to NMDA The receptor's channel plays a key role in the process of blocking the cavity and blocking the channel

Doctoral students Zhang Youyi and Zhang Tongtong of the Center of Excellence for Brain Intelligence of the Chinese Academy of Sciences and Associate Professor Ye Fei of Zhejiang Sci-Tech University are the co-first authors of the paper.

Figure note (A) Cryo-electron microscopic three-dimensional structure of human GluN1-GluN2A NMDA receptor bound to ketamine

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