In a study published in NatureDr. Zhu Shujia’s laboratory researchers at the Institute of Neuroscience, Center for Excellence in Brain Science and Intelligence Technology, Chinese Academy of Sciences (CAS), along with Dr. Luo Cheng’s team at the Shanghai Materia Medica Institute in CAS. Revealed the structural basis of the antidepressant ketamine action on human N-methyl-d-aspartic acid (NMDA) receptors. This finding provided a structural basis for ketamine binding and action on human NMDA receptors, paving the way for future development of ketamine-based antidepressants.
Ketamine, a new fast-acting antidepressant, can quickly relieve the core symptoms of depression and is also effective in patients with treatment-resistant depression. This discovery is the most important breakthrough in the field of antidepressants. However, ketamine can cause side effects of severe psychotomimetics, such as dissociative effects, and can be abused as an entertainment drug that limits its clinical use. Therefore, there is growing scientific and clinical interest in the development of fast-acting antidepressants with few side effects.
In previous studies, ketamine as a pore blocker of the NMDA receptor, an important glutamate-dependent ion channel in the brain, regulates synaptic plasticity and further relieves stress induction on the postsynaptic membrane. It has been shown that it can inhibit the channel activity of NMDA receptors in. Spinal loss in the cortex and hippocampus. Therefore, in the development of ketamine-based antidepressants, it is important to explain the binding site of ketamine at the NMDA receptor and the structural basis of the action of ketamine on the NMDA receptor.
In this study, researchers determined the cryo-EM structure of the human GluN1-GluN2A NMDA receptor complexed with ketamine and discovered an electron density map of ketamine in the transmembrane domain of the NMDA receptor.
The results confirmed that the ketamine binding pocket was in the central vestibule between the channel gate and the selective filter. The vestibule is formed by hydrophobic valine (V644 of the GluN1 subunit) and leucine (L642 of the GluN2A subunit), and the upper and lower parts of the vestibule are formed by polar threonine and asparagine, respectively.
To gain more insight into the interaction of ketamine with residues around the vestibule, they ran molecular dynamics simulations to calculate the movement of ketamine at the binding site.
The results show that L642 of GluN2A made the largest contribution to the relative binding energy during ketamine binding via hydrophobic interaction, whereas N616 of GluN1 formed a hydrogen bond with ketamine among the lower three asparagines. I showed that. These two amino acids, GluN2A L642 and GluN1 N616, have been identified as important residues that form hydrophobic interactions and hydrogen bonds with ketamine, respectively. In addition, mutations at these two important residues reduced the efficacy of ketamine in blocking NMDA receptor channel activity.
This study reveals a ketamine binding pocket in the central vestibule of the NMDA receptor, where the hydrophobic interaction of L642 with GluN2A and the hydrogen bond formed with N616 of GluN1 stabilize the ketamine binding of the NMDA receptor. Further verified that it is essential for.This discovery paved the way for future development KetamineBase antidepressant.
Major depressive disorder affects about 6-16% of the world’s population and even leads to suicide. Antidepressants that target monoamines require long-term treatment over weeks or months and are ineffective in one-third of patients.
Youyi Zhang et al, Structural basis for ketamine action on human NMDA receptors, Nature (2021). DOI: 10.1038 / s41586-021-03769-9
Chinese Academy of Sciences
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Structural basis of the action of the antidepressant ketamine on human NMDA receptors
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