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 DOI: 10.1038/s41594-026-01839-y (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Structural study with site-directed mutagenesis and structure-activity relationship analysis Peer reviewed |
|---|---|
| Population | Human opioid receptors in structural studies |
| Topics | Ketamine Esketamine |
| Keywords | Phencyclidine Opioid receptor Psychotomimetic Pharmacology Nmda receptor Drug discovery Mechanism of action |
| Key points | Ketamine and phencyclidine can directly bind to and activate human opioid receptors, with ketamine showing more notable binding dynamics at the orthosteric site. |
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.