Ketamine is a non-competitive channel blocker of N-methyl-d-aspartate (NMDA) receptors¹. A single sub-anaesthetic dose of ketamine produces rapid (within hours) and long-lasting antidepressant effects in patients who are resistant to other antidepressants^2,3. Ketamine is a racemic mixture containing equal parts of (R)- and (S)-ketamine, with the (S)-enantiomer having greater affinity for the NMDA receptor⁴. Here we describe the cryo-electron microscope 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 showed that S-ketamine moves between two distinct locations within the binding pocket. Two amino acids—leucine 642 on GluN2A (homologous to leucine 643 on GluN2B) and asparagine 616 on GluN1—were identified as key residues that form hydrophobic and hydrogen-bond interactions with ketamine, and mutations at these residues reduced the potency of ketamine in blocking NMDA receptor channel activity. These findings show structurally how ketamine binds to and acts on human NMDA receptors, and pave the way for the future development of ketamine-based antidepressants.

氯胺酮是N-甲基-d-天冬氨酸 (NMDA) 受体¹的非竞争性通道阻滞剂。单次亚麻醉剂量的氯胺酮可在对其他抗抑郁药耐药的患者中产生快速（数小时内）和持久的抗抑郁作用^2,3。氯胺酮是一种外消旋混合物，含有等量的 ( R )- 和 ( S )- 氯胺酮，其中 ( S )- 对映异构体对 NMDA 受体⁴具有更大的亲和力。在这里，我们描述了与S复合的人 GluN1–GluN2A 和 GluN1–GluN2B NMDA 受体的低温电子显微镜结构- 氯胺酮、甘氨酸和谷氨酸。两个电子密度图都在通道门和选择性过滤器之间的中央前庭中揭示了S-氯胺酮的结合袋。分子动力学模拟显示S -氯胺酮在结合口袋内的两个不同位置之间移动。两个氨基酸——GluN2A 上的亮氨酸 642（与 GluN2B 上​​的亮氨酸 643 同源）和 GluN1 上的天冬酰胺 616——被确定为与氯胺酮形成疏水和氢键相互作用的关键残基，这些残基的突变降低了氯胺酮阻断的效力NMDA 受体通道活性。这些发现从结构上展示了氯胺酮如何结合并作用于人类 NMDA 受体，并为未来开发基于氯胺酮的抗抑郁药铺平了道路。