Depression affects more than 264 million people worldwide and is a major contributor to the overall global burden of disease. The pathophysiology of depression remains largely unknown and there is a significant need for development of novel and more efficacious antidepressant treatments.Ketamine is a non-competitive channel blocker of N-Methyl-D-Aspartate (NMDA) receptor. A single sub-anesthetic dose of ketamine produces rapid (within hours) and long-lasting antidepressant effects in patients who are resistant to other antidepressants, which is arguably the most striking breakthrough in the field of depression. Ketamine is a racemic mixture of S- and R-ketamine enantiomers, with S-ketamine isomer as the more active antidepressant.
Dr.Shujia Zhu and her group from Chinese Academy of Sciences has resolved the cryo-EM 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 revealed that S-ketamine displays motions between two distinct locations within the binding pocket. Moreover, two amino acids, Leu642 on GluN2A (homologous Leu643 on GluN2B) and Asn616 on GluN1, were identified as key residues forming hydrophobic and hydrogen-bond interactions with ketamine, and mutations at these identified residues led to the reduced potency of ketamine in blocking the NMDA receptor channel activity.
Discuss cryo-EM structures of human GluN1-GluN2A and GluN1-GluN2B NMDA receptors in complex with S-ketamine and agonists (glycine and glutamate)
Discuss combined structural findings with in silico and electrophysiological studies in NMDA receptors functional insights
Describe and learn structural basis of ketamine binding and action on human NMDA receptors, and how these findings pave the way for future development of NMDA receptor-based antidepressants
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