Structural characterization of kappa-opioid receptor dimer in complex with two G proteins.
Yuxi Zhao, Chanjuan Xu, Yue Wang, Hong Shan, Jing Wang, Yuxuan Liu, Xin Luo, Junrui Li, Mingyang Li, Yini Liu, Kai Wu, Bryan L. Roth, Xi-Ping Huang, H Eric Xu, Jianfeng Liu, Youwen Zhuang
Nature Communications May 29, 2026 DOI: 10.1038/s41467-026-73615-x (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Structural and pharmacological study (cryo-electron microscopy with cell-based assays) Peer reviewed |
|---|---|
| Population | HEK293 cells and purified receptor protein preparations |
| Intervention | Salvinorin A |
| Keywords | Animals Humans Diterpenes, clerodane Gtp-binding proteins Receptors, opioid, kappa Cryoelectron microscopy Protein binding Models, molecular Protein multimerization Hek293 cells |
| Key points | The authors report that κOR forms a stable parallel dimer in living cells that recruits two Gi proteins, and that dimerization increases both the potency and efficacy of Gi recruitment. Salvinorin A binds similarly to monomeric and dimeric κOR, and Y3127.35 is identified as a critical selectivity determinant across opioid receptors. |
Abstract
The κ-opioid receptor (κOR) represents a promising non-addictive analgesic target due to its critical role in pain and reward pathways. Despite evidence of κOR dimerization, its molecular basis and pharmacological significance remain elusive. Here, we demonstrate stable κOR dimer formation in living cells and present cryo-electron microscopy structures of salvinorin A-bound κOR dimer complexed with two Gi proteins, revealing a parallel assembly distinct from previously characterized GPCR dimers that engage only single G protein. Multiple membrane lipids are positioned at the TM1-Helix 8 interface, where they make extensive contacts with both protomers and may contribute to the stability of the κOR dimer. Importantly, dimerization significantly enhances Gi protein recruitment to κOR in both potency and efficacy. We also demonstrate that salvinorin A, a non-nitrogenous agonist, binds similarly in monomeric and dimeric κOR, and identify Y3127.35 as a critical selectivity determinant across opioid receptors. These findings expand our understanding of opioid receptor pharmacology and signaling, providing a foundation for developing superior κOR-targeted therapeutics for pain and related disorders.