echemi logo
Product
  • Product
  • Supplier
  • Inquiry
    Home > Biochemistry News > Biotechnology News > Chinese Academy of Sciences "Nature" reveals the molecular mechanism of the antidepressant ketamine targeting human NMDA receptors

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

    • Last Update: 2021-07-30
    • Source: Internet
    • Author: User
    Search more information of high quality chemicals, good prices and reliable suppliers, visit www.echemi.com

      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".
    Completed in cooperation with the Zhu Shujia research group of the Intelligent Technology Excellence Innovation Center (Neuroscience Institute)

    .
    This study analyzed the three-dimensional structure of NMDA receptor binding to the fast antidepressant ketamine through cryo-electron microscopy, determined the binding site of ketamine on the NMDA receptor, and further analyzed the binding mode of ketamine to the receptor through molecular dynamics simulation.
    Combined with electrophysiological function experiments, the molecular basis of ketamine binding to NMDA receptors is clarified

    .
    This research provides an important basis for the research and development of new antidepressants that target NMDA receptors

    .

      Depression affects more than 300 million people worldwide, and nearly 800,000 depressed patients commit suicide every year
    .
    Traditional antidepressants mostly act on the monoaminergic nervous system, and require continuous medication for several weeks or even months to take effect, and they have no therapeutic effect on one-third of patients with refractory depression

    .
    Ketamine is a new type of antidepressant with rapid onset of action.
    A sub-anaesthetic dose of the drug can significantly improve the patient's negative symptoms such as depression and low self-evaluation within a few hours, and even weaken the patient's suicidal ideation, especially for refractory depression It has a therapeutic effect and is the most important discovery in the field of antidepressant in recent decades

    .
    However, ketamine can cause side effects such as dissociative hallucinations, and has the risk of being abused as a recreational drug, which greatly limits its clinical application
    .
    Therefore, the development of new antidepressants with less side effects and quick onset of action has always been the direction of many scientists around the world

    .

      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 turn, it restores the synaptic damage in the cortex and hippocampus caused by chronic stress

    .
    Therefore, to analyze the binding site of ketamine on the NMDA receptor, and to clarify how ketamine interacts with the NMDA receptor, is of great significance for the design of new antidepressants based on the structure of the ketamine/NMDA receptor complex

    .

      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.
    These two NMDA receptors are the most abundantly expressed in the adult mammalian brain.
    Subtype

    .
    The electron cloud density map of ketamine was found in the transmembrane region of the NMDA receptor, which confirmed that the binding site of ketamine was in the cavity between the gated ion channel and the selective filter

    .
    The top and bottom of the cavity are composed of the polar amino acids threonine and asparagine, respectively, and the middle of the cavity is composed of the hydrophobic amino acids threonine and leucine

    .

      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.
    Bottom) "Two conformations, and cryo-electron microscopy captured the "upper" conformation

    .
    Furthermore, the researchers found that GluN2A-L642 contributes the most to the binding energy of ketamine through the analysis of the free energy of binding.
    Its hydrophobic side chain can form a hydrophobic interaction with ketamine.
    At the same time, it was found that GluN1-N616 would form a hydrogen bond with ketamine

    .
    Furthermore, Zhu Shujia’s team found through point mutation screening and electrophysiological experiments that mutations at these two sites significantly affect the effectiveness of ketamine in inhibiting the activity of NMDA receptor channels, further confirming GluN1-N616 and GluN2A-L642 (homologous GluN2B-L643) It is a key amino acid involved in the binding of ketamine and plays an important role in the process of ketamine inhibiting channel activity

    .

      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
    .
    The study further explored the similarities and differences between the chiral isomers R-ketamine and S-ketamine in terms of binding and molecular mechanisms

    .
    This series of discoveries provides an important basis for the research and development of new antidepressants based on the structure of NMDA receptors

    .

      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.
    Researcher Zhu Shujia from the Center for Brain Intelligence Excellence of the Chinese Academy of Sciences and researcher Luo Cheng from the Shanghai Institute of Materia Medica of the Chinese Academy of Sciences are the co-corresponding authors of the paper

    .
    This work was strongly supported by the Bioimaging Center of the Institute of Biophysics, Chinese Academy of Sciences, and was funded by the National Natural Science Foundation of China, the Chinese Academy of Sciences and Shanghai

    .

    Figure note (A) Cryo-electron microscopic three-dimensional structure of human GluN1-GluN2A NMDA receptor bound to ketamine
    .
    (B) The key amino acid in the cavity of the ketamine binding site

    .
    (C) The binding energy contribution of amino acids around ketamine and the frequency of hydrogen bond formation during the molecular dynamics simulation

    .
    (D) Ketamine dose-response curve of wild-type and key site mutation NMDA receptors

    .

      Full text link: https:// 

    This article is an English version of an article which is originally in the Chinese language on echemi.com and is provided for information purposes only. This website makes no representation or warranty of any kind, either expressed or implied, as to the accuracy, completeness ownership or reliability of the article or any translations thereof. If you have any concerns or complaints relating to the article, please send an email, providing a detailed description of the concern or complaint, to service@echemi.com. A staff member will contact you within 5 working days. Once verified, infringing content will be removed immediately.
    Related Articles

    Contact Us

    The source of this page with content of products and services is from Internet, which doesn't represent Echemi's opinion. If you have any queries, please write to service@echemi.com. It will be replied within 5 days.

    Moreover, if you find any instances of plagiarism from the page, please send email to service@echemi.com with relevant evidence.