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Structural basis of GABA reuptake inhibition
Nature ( IF 64.8 ) Pub Date : 2022-06-08 , DOI: 10.1038/s41586-022-04814-x
Zenia Motiwala 1, 2 , Nanda Gowtham Aduri 1, 2 , Hamidreza Shaye 1, 3, 4 , Gye Won Han 1, 3 , Jordy Homing Lam 1, 5 , Vsevolod Katritch 1, 3, 5 , Vadim Cherezov 1, 2, 3 , Cornelius Gati 1, 2, 3
Affiliation  

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.



中文翻译:

GABA 再摄取抑制的结构基础

γ-氨基丁酸 (GABA) 转运体 1 (GAT1) 1通过清除突触小泡释放的抑制性神经递质 GABA 的突触间隙来调节中枢神经系统的神经元兴奋。通过抑制 GABA 再摄取转运蛋白来提高突触间隙中 GABA 的水平,是治疗癫痫等神经系统疾病的既定策略2。在这里,我们确定了全长野生型人 GAT1 与其临床使用的抑制剂噻加宾3复合物的冷冻电子显微镜结构,有序部分仅为 60 kDa。我们的结构表明,噻加宾通过阻断 GABA 释放途径的细胞内门,将 GAT1 锁定在向内开放的构象中,从而抑制神经递质的摄取。我们的结果提供了对 tiagabine 对 GAT1 的混合型抑制的见解,tiagabine 是一种重要的抗惊厥药物。其药效学特征,经我们的实验数据证实,表明噻加宾最初与外向开放构象中的底物结合位点结合,而我们的结构显示药物使转运蛋白在向内开放构象中停滞,与两步法一致抑制机制4. 所呈现的 GAT1 结构对这种重要的神经递质转运体的生物学和药理学提供了重要的见解,并为神经调节剂的合理设计提供了蓝图,以及移动具有挑战性的膜的单粒子冷冻电子显微镜中被认为可能的边界蛋白质。

更新日期:2022-06-08
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