6M0F

X-ray structure of Drosophila dopamine transporter with subsiteB mutations (D121G/S426M) in substrate-free form

6M0F の概要

• エントリーDOI: 10.2210/pdb6m0f/pdb
• 関連するPDBエントリー: 4M48 4XNX 4XP1 4XPH
• 分子名称: Sodium-dependent dopamine transporter, Antibody fragment (9D5) Light chain, Antibody fragment (9D5) heavy chain, ... (8 entities in total)
• 機能のキーワード: neurotransmitter transporter, antibody fragment, membrane protein
• 由来する生物種: Drosophila melanogaster (Fruit fly); 詳細
• タンパク質・核酸の鎖数: 3
• 化学式量合計: 107821.35

構造登録者

Shabareesh, P.,Mallela, A.K.,Joseph, D.,Penmatsa, A. (登録日: 2020-02-21, 公開日: 2021-02-17, 最終更新日: 2024-11-13)

主引用文献

Pidathala, S.,Mallela, A.K.,Joseph, D.,Penmatsa, A.
Structural basis of norepinephrine recognition and transport inhibition in neurotransmitter transporters.
Nat Commun, 12:2199-2199, 2021

PubMed Abstract: Norepinephrine is a biogenic amine neurotransmitter that has widespread effects on alertness, arousal and pain sensation. Consequently, blockers of norepinephrine uptake have served as vital tools to treat depression and chronic pain. Here, we employ the Drosophila melanogaster dopamine transporter as a surrogate for the norepinephrine transporter and determine X-ray structures of the transporter in its substrate-free and norepinephrine-bound forms. We also report structures of the transporter in complex with inhibitors of chronic pain including duloxetine, milnacipran and a synthetic opioid, tramadol. When compared to dopamine, we observe that norepinephrine binds in a different pose, in the vicinity of subsite C within the primary binding site. Our experiments reveal that this region is the binding site for chronic pain inhibitors and a determinant for norepinephrine-specific reuptake inhibition, thereby providing a paradigm for the design of specific inhibitors for catecholamine neurotransmitter transporters.

PubMed: 33850134
DOI: 10.1038/s41467-021-22385-9

実験手法

X-RAY DIFFRACTION (3.3 Å)