8BLB

Human serotonin 5-HT3A receptor in complex with vortioxetine (nanodiscs, ECD, active/distorted conformation)

8BLB の概要

• エントリーDOI: 10.2210/pdb8blb/pdb
• EMDBエントリー: 16105
• 分子名称: 5-hydroxytryptamine receptor 3A, 2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose, 2-acetamido-2-deoxy-beta-D-glucopyranose, ... (4 entities in total)
• 機能のキーワード: human pentameric ligand-gated ion channel, human serotonin receptor, membrane protein
• 由来する生物種: Homo sapiens (human)
• タンパク質・核酸の鎖数: 5
• 化学式量合計: 267703.90

構造登録者

Lopez-Sanchez, U.,Nury, H. (登録日: 2022-11-09, 公開日: 2024-05-15, 最終更新日: 2025-07-09)

主引用文献

Lopez-Sanchez, U.,Munro, L.J.,Ladefoged, L.K.,Pedersen, A.J.,Brun, C.C.,Lyngby, S.M.,Baud, D.,Juillan-Binard, C.,Pedersen, M.G.,Lummis, S.C.R.,Bang-Andersen, B.,Schiott, B.,Chipot, C.,Schoehn, G.,Neyton, J.,Dehez, F.,Nury, H.,Kristensen, A.S.
Structural determinants for activity of the antidepressant vortioxetine at human and rodent 5-HT 3 receptors.
Nat.Struct.Mol.Biol., 31:1232-1242, 2024

PubMed Abstract: Vortioxetine (VTX) is a recently approved antidepressant that targets a variety of serotonin receptors. Here, we investigate the drug's molecular mechanism of operation at the serotonin 5-HT receptor (5-HTR), which features two properties: VTX acts differently on rodent and human 5-HTR, and VTX appears to suppress any subsequent response to agonists. Using a combination of cryo-EM, electrophysiology, voltage-clamp fluorometry and molecular dynamics, we show that VTX stabilizes a resting inhibited state of the mouse 5-HTR and an agonist-bound-like state of human 5-HTR, in line with the functional profile of the drug. We report four human 5-HTR structures and show that the human receptor transmembrane domain is intrinsically fragile. We also explain the lack of recovery after VTX administration via a membrane partition mechanism.

PubMed: 38698207
DOI: 10.1038/s41594-024-01282-x

実験手法

ELECTRON MICROSCOPY (3.3 Å)