8WTX

Cryo-EM structure of noradrenaline transporter in complex with bupropion

8WTX の概要

• エントリーDOI: 10.2210/pdb8wtx/pdb
• EMDBエントリー: 37845
• 分子名称: Sodium-dependent noradrenaline transporter, (2~{R})-2-(~{tert}-butylamino)-1-(3-chlorophenyl)propan-1-one (2 entities in total)
• 機能のキーワード: noradrenaline transporter, inhibition, bupropion, structural protein
• 由来する生物種: Homo sapiens (human)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 64040.85

構造登録者

Zhao, Y.,Hu, T.,Yu, Z. (登録日: 2023-10-19, 公開日: 2024-08-07, 最終更新日: 2024-10-16)

主引用文献

Hu, T.,Yu, Z.,Zhao, J.,Meng, Y.,Salomon, K.,Bai, Q.,Wei, Y.,Zhang, J.,Xu, S.,Dai, Q.,Yu, R.,Yang, B.,Loland, C.J.,Zhao, Y.
Transport and inhibition mechanisms of the human noradrenaline transporter.
Nature, 632:930-937, 2024

PubMed Abstract: The noradrenaline transporter (also known as norepinephrine transporter) (NET) has a critical role in terminating noradrenergic transmission by utilizing sodium and chloride gradients to drive the reuptake of noradrenaline (also known as norepinephrine) into presynaptic neurons. It is a pharmacological target for various antidepressants and analgesic drugs. Despite decades of research, its structure and the molecular mechanisms underpinning noradrenaline transport, coupling to ion gradients and non-competitive inhibition remain unknown. Here we present high-resolution complex structures of NET in two fundamental conformations: in the apo state, and bound to the substrate noradrenaline, an analogue of the χ-conotoxin MrlA (χ-MrlA), bupropion or ziprasidone. The noradrenaline-bound structure clearly demonstrates the binding modes of noradrenaline. The coordination of Na and Cl undergoes notable alterations during conformational changes. Analysis of the structure of NET bound to χ-MrlA provides insight into how conotoxin binds allosterically and inhibits NET. Additionally, bupropion and ziprasidone stabilize NET in its inward-facing state, but they have distinct binding pockets. These structures define the mechanisms governing neurotransmitter transport and non-competitive inhibition in NET, providing a blueprint for future drug design.

PubMed: 39085602
DOI: 10.1038/s41586-024-07638-z

実験手法

ELECTRON MICROSCOPY (2.9 Å)