Structure and allosteric inhibition of excitatory amino acid transporter 1.
Structure and allosteric inhibition of excitatory amino acid transporter 1.
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DOI：
10.1038/nature22064
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发表时间：
2017-04-27
期刊：
影响因子：
64.8
通讯作者：
Reyes N
中科院分区：
文献类型：
--
作者：
Canul-Tec JC;Assal R;Cirri E;Legrand P;Brier S;Chamot-Rooke J;Reyes N
溶质载体1（SLC 1）转运蛋白家族的人类成员摄取大脑中的兴奋性神经递质和外周器官中的氨基酸。它们的功能失调与神经退行性疾病和癌症有关。在这里，我们提出了第一个晶体结构的热稳定的人SLC 1转运蛋白，兴奋性氨基酸转运蛋白1（EAAT 1），有和没有变构和竞争性抑制剂绑定。这些结构显示了人类转运蛋白的新结构特征，包括在转运功能中具有潜在作用的胞内和胞外域，以及脂质和翻译后修饰的调节。在结构中的抑制剂的协调和通过氢-氘交换质谱法测量的转运动力学的变化，揭示了抑制的变构机制，由此转运蛋白被锁定在运输循环的面向外的状态。我们的研究结果为人类SLC 1转运蛋白的功能和药理学的分子机制提供了前所未有的见解。
Human members of the solute carrier 1 (SLC1) family of transporters take up excitatory neurotransmitters in the brain and amino acids in peripheral organs. Dysregulation of their functions is associated to neurodegenerative disorders and cancer. Here we present the first crystal structures of a thermostabilized human SLC1 transporter, the excitatory amino acid transporter 1 (EAAT1), with and without allosteric and competitive inhibitors bound. The structures show novel architectural features of the human transporters, including intra- and extracellular domains with potential roles in transport function, as well as regulation by lipids and post-translational modifications. The coordination of the inhibitor in the structures and the change in the transporter dynamics measured by hydrogen-deuterium exchange mass spectrometry, reveal an allosteric mechanism of inhibition, whereby the transporter is locked in the outward-facing states of the transport cycle. Our results provide unprecedented insights into the molecular mechanisms of function and pharmacology of human SLC1 transporters.