9PA4

(S)-ketamine bound kappa-opioid receptor in complex with Gi1

Summary for 9PA4

• Entry DOI: 10.2210/pdb9pa4/pdb
• EMDB information: 71432
• Descriptor: Kappa-type opioid receptor, Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1, Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2, ... (6 entities in total)
• Functional Keywords: kappa opioid receptor, signaling protein
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 5
• Total formula weight: 147463.98

Authors

Jiang, Q.R.,Han, J.M.,Fay, J.F.,Che, T. (deposition date: 2025-06-25, release date: 2026-07-01)

Primary citation

Jiang, Q.,Han, J.,Fine, E.J.,Ramos-Gonzalez, N.,Rangari, V.A.,Ruiz, M.V.,Critz, M.L.,Suomivuori, C.M.,Wang, J.,Albert, T.L.,Whiddon, K.,Li, K.,Robertson, M.J.,Huang, X.P.,Land, B.B.,Majumdar, S.,Fay, J.F.,Dror, R.O.,Che, T.
Structural basis of opioid receptor activation by PCP and ketamine.
Nat.Struct.Mol.Biol., 2026

PubMed 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.

PubMed: 42332075
DOI: 10.1038/s41594-026-01839-y

Experimental method

ELECTRON MICROSCOPY (2.5 Å)