9LL8

Psilocin-bound Serotonin 2A (5-HT2A) receptor-Gi complex

Summary for 9LL8

• Entry DOI: 10.2210/pdb9ll8/pdb
• EMDB information: 63193
• Descriptor: 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, Guanine nucleotide-binding protein G(i) subunit alpha-1, ... (7 entities in total)
• Functional Keywords: complex, agonist, membrane protein
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 4
• Total formula weight: 138640.60

Authors

Xu, Z.,Shao, Z.H. (deposition date: 2025-01-17, release date: 2026-01-14, Last modification date: 2026-02-18)

Primary citation

Xu, Z.,Wang, H.,Yu, J.,Deng, Y.,Tian, X.,Ni, R.,Xia, F.,Yang, L.,Xu, C.,Zhang, L.,Luo, R.,Chen, P.,Zhang, X.,Liu, Y.,Hou, J.,Zhang, M.,Chen, S.,Su, L.,Sun, H.,He, Y.,Chen, D.,Chen, X.,Miao, Z.,Xie, J.,Liu, X.,Zhao, J.,Ke, B.,Tian, X.,Zeng, L.,Zhang, L.,Tang, X.,Yang, S.,Liu, J.,Wang, X.,Yan, W.,Shao, Z.
Psychedelics elicit their effects by 5-HT 2A receptor-mediated G i signalling.
Nature, 2026

PubMed Abstract: 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.

PubMed: 41606342
DOI: 10.1038/s41586-025-10061-7

Experimental method

ELECTRON MICROSCOPY (2.62 Å)