Structural basis of opioid receptor activation by PCP and ketamine
Qianru Jiang, Jianming Han, Eve Fine, Nokomis Ramos‐gonzalez, Vipin Ashok Rangari, Micaela V. Ruiz, Madalyn L. Critz, Carl‐mikael Suomivuori, Jing Wang, Talia L. Albert, Kyle Whiddon, Kunpeng Li, Michael J. Robertson, Xi‐ping Huang, Benjamin B. Land, Susruta Majumdar, Jonathan F. Fay, Ron O. Dror, Tao Che
Nature Structural & Molecular Biology June 22, 2026 Peer reviewed DOI: 10.1038/s41594-026-01839-y via OpenAlex
Summary
Ketamine provides rapid relief for treatment-resistant depression and severe pain, with effects that may extend beyond its antagonism of the N-methyl-D-aspartate receptor. Structural evidence shows that ketamine and phencyclidine can bind and activate opioid receptors, with key motifs identified for their recognition and efficacy. Ketamine exhibits distinct binding dynamics compared to phencyclidine at the opioid receptor, suggesting a unique pharmacological profile that is important for understanding its clinical versatility.
Study at a glance
| Key finding | Ketamine and phencyclidine can directly bind and activate opioid receptors, with ketamine showing notable differences in binding dynamics compared to phencyclidine. |
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Abstract
Ketamine offers rapid relief for treatment-resistant depression and severe pain in the clinic, providing immediate benefits that traditional medications often fail to deliver. While its antagonistic action at the N-methyl-D-aspartate receptor (NMDAR) is a key mechanism, ketamine's dual nature as both a promising treatment and a drug with abuse potential suggests its therapeutic effects extend beyond NMDAR inhibition. Here we provide structural evidence of human opioid receptors bound to ketamine and its parent analog phencyclidine (PCP), supporting that both ligands can directly bind and activate opioid receptors. The structures, together with site-directed mutagenesis and structure-activity relationship studies, identify key motifs involved in ketamine and PCP recognition and efficacy modulation. Furthermore, we determine the structure of the ligand-free state of human κ opioid receptor, revealing molecular details before ligand engagement. Compared to PCP, ketamine displays more notable binding dynamics in the orthosteric site that may contribute to its unique pharmacology at opioid receptors. Our findings highlight the importance of including opioid receptors to fully understand ketamine's versatility in clinical settings.