9VJE

Cryo-EM structure of 5-HT1AR-GoA in complex with buspirone

Summary for 9VJE

• Entry DOI: 10.2210/pdb9vje/pdb
• EMDB information: 65110
• Descriptor: Guanine nucleotide-binding protein G(o) subunit alpha, 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, ... (8 entities in total)
• Functional Keywords: signal transduction, membrane protein
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 5
• Total formula weight: 177073.47

Authors

Wang, C.,Cao, C. (deposition date: 2025-06-19, release date: 2025-11-12, Last modification date: 2026-04-01)

Primary citation

Wang, C.,Zhang, N.,Shao, Y.,Li, T.,Zhang, M.,Gao, M.,Liang, Y.,Wang, Y.,Xue, T.,Shi, Y.,Chen, H.,Cao, C.
Pathway-selective 5-HT 1A R agonist as a rapid antidepressant strategy.
Cell, 188:7222-7237.e24, 2025

PubMed Abstract: Presynaptic 5-HTR autoreceptors predominantly signal through G protein, mediating feedback inhibition that hampers the therapeutic efficacy of conventional antidepressants. By contrast, postsynaptic heteroreceptors mainly couple to G, which promotes antidepressant responses. However, selectively activating heteroreceptors while bypassing the negative feedback induced by autoreceptors remains a significant challenge. Here, we characterized the G subtype signaling profiles of 5-HTR and determined its structures in complex with six agonists and three distinct G family proteins: G, G, and G. Combined with functional analysis, we elucidated the mechanisms underlying diverse agonist recognition modes and G subtype signaling selectivity of 5-HTR. Furthermore, we designed a pathway-selective agonist, TMU4142, which exhibits high G activity while minimizing G activation. Remarkably, TMU4142 demonstrated rapid antidepressant-like effects in a mouse model of depression. Collectively, these findings suggest that distinguishing heteroreceptors from autoreceptors based on their distinct downstream G signaling pathways could be a promising strategy to develop fast-acting antidepressants.

PubMed: 41232528
DOI: 10.1016/j.cell.2025.10.022

Experimental method

ELECTRON MICROSCOPY (2.47 Å)