Structural basis of opioid receptor activation by PCP and ketamine PMID: 42332075

ADC Targets in Oncology

2026-04-10

Structural basis of opioid receptor activation by PCP and ketamine

Nat Struct Mol Biol. 2026 Jun 22. doi: 10.1038/s41594-026-01839-y.

Qianru Jiang ^# ¹ , Jianming Han ^# ¹ , Eve J Fine ^# ² ³ ⁴ ⁵ , Nokomis Ramos-Gonzalez ¹ , Vipin Ashok Rangari ¹ , Micaela V Ruiz ⁶ , Madalyn L Critz ⁶ , Carl-Mikael Suomivuori ³ ⁴ ⁵ ⁷ , Jing Wang ⁸ , Talia L Albert ⁸ , Kyle Whiddon ⁹ , Kunpeng Li ⁹ , Michael J Robertson ¹⁰ , Xi-Ping Huang ⁸ , Benjamin B Land ⁶ , Susruta Majumdar ¹ , Jonathan F Fay ¹¹ , Ron O Dror ¹² ¹³ ¹⁴ , Tao Che ¹⁵

Affiliations

1. Center for Clinical Pharmacology, Department of Anesthesiology, Washington University School of Medicine, Saint Louis, MO, USA.
2. Department of Bioengineering, Stanford University, Stanford, CA, USA.
3. Department of Computer Science, Stanford, CA, USA.
4. Departments of Molecular and Cellular Physiology and of Structural Biology, Stanford University School of Medicine, Stanford, CA, USA.
5. Institute for Computational and Mathematical Engineering, Stanford University, Stanford, CA, USA.
6. Department of Pharmacology, UW Center of Excellence in Neurobiology of Addiction, Pain, and Emotion (NAPE), University of Washington, Seattle, WA, USA.
7. Department of Pharmacology, Yale School of Medicine, New Haven, CT, USA.
8. Department of Pharmacology and NIMH Psychoactive Drug Screening Program, UNC Chapel Hill Medical School, Chapel Hill, NC, USA.
9. Department of Pharmacology, Case Western Reserve University, Cleveland, OH, USA.
10. Verna and Marrs McLean Department of Biochemistry and Molecular Pharmacology, Baylor College of Medicine, Houston, TX, USA.
11. Department of Biochemistry and Molecular Biology, University of Maryland Baltimore, Baltimore, MD, USA. [email protected].
12. Department of Computer Science, Stanford, CA, USA. [email protected].
13. Departments of Molecular and Cellular Physiology and of Structural Biology, Stanford University School of Medicine, Stanford, CA, USA. [email protected].
14. Institute for Computational and Mathematical Engineering, Stanford University, Stanford, CA, USA. [email protected].
15. Center for Clinical Pharmacology, Department of Anesthesiology, Washington University School of Medicine, Saint Louis, MO, USA. [email protected].
# Contributed equally.

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.