Nature：GABA再摄取抑制的结构基础

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Nature：GABA再摄取抑制的结构基础

领研网

2022/07/03

论文
论文标题：Structural basis of GABA reuptake inhibition
作者：Zenia Motiwala, Nanda Gowtham Aduri, Hamidreza Shaye, Gye Won Han, Jordy Homing Lam, Vsevolod Katritch, Vadim Cherezov & Cornelius Gati
期刊：Nature
发表时间：2022/06/08
数字识别码：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.

所属学科：
结构生物学

（导读 阿金）γ-氨基丁酸 (GABA) 转运蛋白 1 (GAT1)调控中枢神经系统的神经元兴奋。本研究解析出全长野生型人源GAT1与临床应用抑制剂噻加宾结合复合物的冷冻电镜结构，发现噻加宾在向内打开的构象中锁定GAT1，从而抑制神经递质摄取。该结果为理解通过噻加宾对GAT1进行混合型抑制提供新思路，为合理设计神经调节因子奠定新基础。

文章标签
γ-氨基丁酸 (GABA) 转运蛋白 1 (GAT1)
中枢神经系统
神经元兴奋
冷冻电镜结构
噻加宾
神经递质

https://www.nature.com/articles/s41586-022-04814-x

https://www.linkresearcher.com/t ... 3-9bb7-196930545b09



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