8XB2

Structure of radafaxine-bound state of the human Norepinephrine Transporter

8XB2 の概要

• エントリーDOI: 10.2210/pdb8xb2/pdb
• EMDBエントリー: 38208
• 分子名称: GFP-MBP-solute carrier family 6 member 2,Maltose/maltodextrin-binding periplasmic protein,Sodium-dependent noradrenaline transporter,Maltose/maltodextrin-binding periplasmic protein,Sodium-dependent noradrenaline transporter, 2-acetamido-2-deoxy-beta-D-glucopyranose, Radafaxine (3 entities in total)
• 機能のキーワード: antidepressant, bupropion, transport protein
• 由来する生物種: Homo sapiens (human); 詳細
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 139173.97

構造登録者

Wu, J.X.,Ji, W.M. (登録日: 2023-12-05, 公開日: 2024-07-10, 最終更新日: 2024-11-20)

主引用文献

Ji, W.,Miao, A.,Liang, K.,Liu, J.,Qi, Y.,Zhou, Y.,Duan, X.,Sun, J.,Lai, L.,Wu, J.X.
Substrate binding and inhibition mechanism of norepinephrine transporter.
Nature, 633:473-479, 2024

PubMed Abstract: Norepinephrine transporter (NET; encoded by SLC6A2) reuptakes the majority of the released noradrenaline back to the presynaptic terminals, thereby affecting the synaptic noradrenaline level. Genetic mutations and dysregulation of NET are associated with a spectrum of neurological conditions in humans, making NET an important therapeutic target. However, the structure and mechanism of NET remain unclear. Here we provide cryogenic electron microscopy structures of the human NET (hNET) in three functional states-the apo state, and in states bound to the substrate meta-iodobenzylguanidine (MIBG) or the orthosteric inhibitor radafaxine. These structures were captured in an inward-facing conformation, with a tightly sealed extracellular gate and an open intracellular gate. The substrate MIBG binds at the centre of hNET. Radafaxine also occupies the substrate-binding site and might block the structural transition of hNET for inhibition. These structures provide insights into the mechanism of substrate recognition and orthosteric inhibition of hNET.

PubMed: 39143211
DOI: 10.1038/s41586-024-07810-5

実験手法

ELECTRON MICROSCOPY (3.04 Å)