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-Structure paper
| タイトル | Psychedelics elicit their effects by 5-HT receptor-mediated G signalling. |
|---|---|
| ジャーナル・号・ページ | Nature, Year 2026 |
| 掲載日 | 2026年1月28日 |
著者 | Zheng Xu / Hongshuang Wang / Jingjing Yu / Yue Deng / Xiaowen Tian / Rongjun Ni / Fan Xia / Lingyi Yang / Chanjuan Xu / Liting Zhang / Renxuan Luo / Peipei Chen / Xiaoyu Zhang / Yuxuan Liu / Jingyu Hou / Miyuan Zhang / Shasha Chen / Lantian Su / Hui Sun / Yixiao He / Dandan Chen / Xiaoting Chen / Zhuang Miao / Jie Xie / Xinlei Liu / Jie Zhao / Bowen Ke / Xiaohe Tian / Linan Zeng / Lingli Zhang / Xiangdong Tang / Shengyong Yang / Jianfeng Liu / Xiaohui Wang / Wei Yan / Zhenhua Shao / ![]() |
| PubMed 要旨 | Psychedelics are undergoing a renaissance as potential therapy for psychiatric disorders, with more than 200 clinical trials being studied across several countries. However, the precise mechanisms by ...Psychedelics are undergoing a renaissance as potential therapy for psychiatric disorders, with more than 200 clinical trials being studied across several countries. However, the precise mechanisms by which these drugs bring about benefits and the potential clinical risks are not yet fully understood. The serotonin 2A receptor (5-HTR) was reported to be a G-coupled receptor and the primary interoceptive target of psychedelics. Here we compared psychedelics and their non-hallucinogenic analogues (nHAs) using in vitro and in vivo approaches, finding that 5-HTR-mediated non-canonical G signalling is essential for hallucinogenic effect. We further presented five cryo-electron microscopy structures of 5-HTR-G/G in complex with psychedelics or nHAs. Structural analysis and pharmacological investigation revealed that a special contact between nHAs with 5-HTR mediated the signalling bias. Building on this insight, we identified a 2,5-dimethoxy-4-iodoamphetamine derivative, DOI-NBOMe, which exhibits potent and selective G-biased activity, and demonstrates promising therapeutic effects in mouse models without hallucinogenic effect. Our finding uncovers the functional mechanisms underlying the G signalling mediated by 5-HTR and provides valuable insights for designing psychedelic-based drugs with minimized risk from hallucinogenic effects. |
リンク | Nature / PubMed:41606342 |
| 手法 | EM (単粒子) |
| 解像度 | 2.62 - 3.27 Å |
| 構造データ | EMDB-63192, PDB-9ll7: EMDB-63193, PDB-9ll8: EMDB-63194, PDB-9ll9: EMDB-63195, PDB-9lla: EMDB-63196, PDB-9llb: |
| 化合物 | ![]() ChemComp-CLR: ![]() PDB-1ek5: ![]() ChemComp-HOH: ![]() ChemComp-91Q: ![]() PDB-1ek8: ![]() PDB-1ela: |
| 由来 |
|
キーワード | MEMBRANE PROTEIN / complex / agonist |
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