7SK2

Human wildtype GABA reuptake transporter 1 in complex with tiagabine, inward-open conformation

7SK2 の概要

• エントリーDOI: 10.2210/pdb7sk2/pdb
• EMDBエントリー: 25170
• 分子名称: Sodium- and chloride-dependent GABA transporter 1, Tiagabine (2 entities in total)
• 機能のキーワード: neurotransmitter transporter, membrane 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: 65262.34

構造登録者

Gati, C.,Motiwala, Z.,Aduri, N.G.,Shaye, H.,Han, G.W.,Cherezov, V. (登録日: 2021-10-19, 公開日: 2022-06-08, 最終更新日: 2025-05-28)

主引用文献

Motiwala, Z.,Aduri, N.G.,Shaye, H.,Han, G.W.,Lam, J.H.,Katritch, V.,Cherezov, V.,Gati, C.
Structural basis of GABA reuptake inhibition.
Nature, 606:820-826, 2022

PubMed Abstract: γ-Aminobutyric acid (GABA) transporter 1 (GAT1) regulates neuronal excitation of the central nervous system by clearing the synaptic cleft of the inhibitory neurotransmitter GABA upon its release from synaptic vesicles. Elevating the levels of GABA in the synaptic cleft, by inhibiting GABA reuptake transporters, is an established strategy to treat neurological disorders, such as epilepsy. Here we determined the cryo-electron microscopy structure of full-length, wild-type human GAT1 in complex with its clinically used inhibitor tiagabine, with an ordered part of only 60 kDa. Our structure reveals that tiagabine locks GAT1 in the inward-open conformation, by blocking the intracellular gate of the GABA release pathway, and thus suppresses neurotransmitter uptake. Our results provide insights into the mixed-type inhibition of GAT1 by tiagabine, which is an important anticonvulsant medication. Its pharmacodynamic profile, confirmed by our experimental data, suggests initial binding of tiagabine to the substrate-binding site in the outward-open conformation, whereas our structure presents the drug stalling the transporter in the inward-open conformation, consistent with a two-step mechanism of inhibition. The presented structure of GAT1 gives crucial insights into the biology and pharmacology of this important neurotransmitter transporter and provides blueprints for the rational design of neuromodulators, as well as moving the boundaries of what is considered possible in single-particle cryo-electron microscopy of challenging membrane proteins.

PubMed: 35676483
DOI: 10.1038/s41586-022-04814-x

実験手法

ELECTRON MICROSCOPY (3.82 Å)