硫加宾
gaba转运蛋白
再摄取
突触裂
神经递质转运体
神经递质
突触小泡
运输机
化学
再摄取抑制剂
药理学
生物物理学
γ-氨基丁酸
神经科学
生物
生物化学
抗惊厥药
小泡
血清素
受体
膜
基因
癫痫
作者
Zenia Motiwala,Nanda G. Aduri,Hamidreza Shaye,Gye Won Han,Jordy Homing Lam,Vsevolod Katritch,Vadim Cherezov,Cornelius Gati
出处
期刊:Nature
[Springer Nature]
日期:2022-06-08
卷期号:606 (7915): 820-826
被引量:35
标识
DOI:10.1038/s41586-022-04814-x
摘要
γ-Aminobutyric acid (GABA) transporter 1 (GAT1)1 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 epilepsy2. Here we determined the cryo-electron microscopy structure of full-length, wild-type human GAT1 in complex with its clinically used inhibitor tiagabine3, 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 inhibition4. 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. Structural determination of GAT1 using cryo-electron microscopy provides insights into the biology and pharmacology of this GABA transporter.
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