Seeing its structure clearly, humans are expected to "perfectly" fight depression

  Ketamine inhibits the key mechanism of NMDA receptor activity.

  News from our newspaper (Chief reporter Xu Qimin) Is there a medicine that can cure the depression that affects more than 300 million people in the world?

This dream that the global medical community has explored for decades has now taken another crucial step toward realization.

  The Zhu Shujia research group of the Center for Excellence in Brain Science and Intelligent Technology of the Chinese Academy of Sciences and the Luo Cheng research group of the Shanghai Institute of Materia Medica, Chinese Academy of Sciences have analyzed the three-dimensional structure of the glutamate-gated ion channel NMDA receptor combined with the fast antidepressant ketamine through cryo-electron microscopy , Determined the binding site of ketamine on the NMDA receptor, and clarified the molecular basis of the binding of ketamine to the NMDA receptor.

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

Recently, the top international academic journal "Nature" published this result online.

  "This research was carried out from a story that my girlfriend told me more than two years ago." Zhu Shujia said that a 70-year-old man in her girlfriend's family kept telling her that she was unwell, but her son and daughter took her to check her body but everything was normal. Six months after he concluded that he was not sick, the old man committed suicide at home.

"Actually, she had severe depression." Zhu Shujia explained that depression is actually an organic disease in the brain. If timely medication, physical and psychological treatments are used, it can be controlled, relieved and even hopefully cured. .

  However, what makes doctors a headache is that there is no antidepressant drug that has the advantages of fast onset, small side effects, and eradicating diseases.

In March 2019, the U.S. Food and Drug Administration approved the marketing of S-ketamine, which was once used as an anesthetic. Within a few hours, patients with severe depression who have been tortured by suicidal thoughts can improve their depression, and the effect of the drug can last for a week or two.

  Traditional antidepressants take several weeks to work and are ineffective for one-third of patients. In contrast, S-ketamine is the most important discovery in the field of antidepressants in recent decades.

However, once it is used improperly, it can easily cause side effects such as dissociative hallucinations and addiction. Since the 1990s, it has been strictly controlled by European and American countries.

  Zhu Shujia hopes to find out the mystery of S-ketamine's antidepressant through detailed protein structure analysis, so as to design a more perfect new antidepressant drug.

"Through cryo-electron microscopy, we obtained a high-definition three-dimensional structure of 3.5 angstroms, and also simulated the process of the dynamic action of molecular drugs." She introduced that there are many subtypes of NMDA receptors, and the research team analyzed S-ketamine and human GluN1 -The structure of the complex of GluN2A and GluN1-GluN2B subtypes, "In the receptor transmembrane region, we found a'pocket', in which S-ketamine binds to the NMDA receptor".

  Interestingly, S-ketamine is not restless in the "pocket" of NMDA receptors and will jump up and down.

Zhu Shujia's team also observed the "sister" R-ketamine, the mirror molecule of S-ketamine, and found that this "sister" is relatively quiet. Although the onset of action is slightly slower than that of S-ketamine, the effect lasts for up to two or three weeks.

It is reported that at present, domestic pharmaceutical companies have carried out clinical research on this molecule.

Zhu Shujia hopes that this result can promote the follow-up research and development of new antidepressant drugs.

  In addition, the joint research team also found that certain genetic mutations can prevent ketamine drugs from binding to NMDA receptors, thereby losing their antidepressant efficacy.

This will also provide theoretical support for personalized and precise treatment of depression.