9VJ69VJ6 の概要
| エントリーDOI | 10.2210/pdb9vj6/pdb |
| EMDBエントリー | 65105 |
| 分子名称 | Guanine nucleotide-binding protein G(i) subunit alpha-3, 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) |
| 機能のキーワード | signal transduction, membrane protein |
| 由来する生物種 | Homo sapiens (human) 詳細 |
| タンパク質・核酸の鎖数 | 5 |
| 化学式量合計 | 177585.53 |
| 構造登録者 | |
| 主引用文献 | 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 Cited by 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: 41232528DOI: 10.1016/j.cell.2025.10.022 主引用文献が同じPDBエントリー |
| 実験手法 | ELECTRON MICROSCOPY (2.62 Å) |
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