7YS6

Cryo-EM structure of the Serotonin 6 (5-HT6) receptor-DNGs-scFv16 complex

7YS6 の概要

• エントリーDOI: 10.2210/pdb7ys6/pdb
• EMDBエントリー: 34073
• 分子名称: 5-hydroxytryptamine receptor 6, 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, ... (6 entities in total)
• 機能のキーワード: gpcr, serotonin receptor, 5-ht6r, cryo-em, constitutive activity, 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: 152647.27

構造登録者

Zhao, Q.Y.,Wang, Y.F.,He, L.,Wang, S.,Cong, Y. (登録日: 2022-08-11, 公開日: 2023-03-29, 最終更新日: 2025-06-18)

主引用文献

He, L.,Zhao, Q.Y.,Qi, J.,Wang, Y.,Han, W.,Chen, Z.,Cong, Y.,Wang, S.
Structural insights into constitutive activity of 5-HT 6 receptor.
Proc.Natl.Acad.Sci.USA, 120:e2209917120-e2209917120, 2023

PubMed Abstract: While most therapeutic research on G-protein-coupled receptors (GPCRs) focuses on receptor activation by (endogenous) agonists, significant therapeutic potential exists through agonist-independent intrinsic constitutive activity that can occur in various physiological and pathophysiological settings. For example, inhibiting the constitutive activity of 5-HTR-a receptor that is found almost exclusively in the brain and mediates excitatory neurotransmission-has demonstrated a therapeutic effect on cognitive/memory impairment associated with several neuropsychiatric disorders. However, the structural basis of such constitutive activity remains unclear. Here, we present a cryo-EM structure of serotonin-bound human 5-HTR-Gs heterotrimer at 3.0-Å resolution. Detailed analyses of the structure complemented by comprehensive interrogation of signaling illuminate key structural determinants essential for constitutive 5-HTR activity. Additional structure-guided mutagenesis leads to a nanobody mimic Gαs for 5-HTR that can reduce its constitutive activity. Given the importance of 5-HTR for a large number of neuropsychiatric disorders, insights derived from these studies will accelerate the design of more effective medications, and shed light on the molecular basis of constitutive activity.

PubMed: 36989299
DOI: 10.1073/pnas.2209917120

実験手法

ELECTRON MICROSCOPY (3 Å)