Crystal structure of a bacterial homologue of Na+/Cl--dependent neurotransmitter transporters
Crystal structure of a bacterial homologue of Na+/Cl--dependent neurotransmitter transporters
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DOI：
10.1038/nature03978
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发表时间：
2005-09-08
期刊：
影响因子：
64.8
通讯作者：
Gouaux, E
中科院分区：
文献类型：
--
作者：
Yamashita, A;Singh, SK;Gouaux, E
Na+/Cl-依赖性转运蛋白通过使用电化学梯度来驱动神经递质（包括生物胺）从突触到神经元和胶质细胞的细胞质的摄取来终止突触传递。这些转运蛋白是治疗性和非法化合物的靶点，它们的功能障碍与多种神经系统疾病有关。在这里，我们提出了这些转运蛋白的细菌同系物从Aquifex aeolicus的晶体结构，在复杂的其基板，亮氨酸，和两个钠离子。蛋白质核心由12个跨膜区段中的前10个组成，其中区段1 - 5通过膜平面中的伪二重轴与6 - 10相关。亮氨酸和钠离子结合在蛋白质核心内，穿过膜双层的一半，在没有水的闭塞部位。亮氨酸和离子结合位点由部分解绕的跨膜螺旋限定，其中主链原子和螺旋偶极子在底物和离子结合中具有关键作用。该结构揭示了这类重要的转运蛋白的结构，阐明了底物结合和离子选择性的决定因素，并定义了外部和内部门。
Na+/Cl--dependent transporters terminate synaptic transmission by using electrochemical gradients to drive the uptake of neurotransmitters, including the biogenic amines, from the synapse to the cytoplasm of neurons and glia. These transporters are the targets of therapeutic and illicit compounds, and their dysfunction has been implicated in multiple diseases of the nervous system. Here we present the crystal structure of a bacterial homologue of these transporters from Aquifex aeolicus, in complex with its substrate, leucine, and two sodium ions. The protein core consists of the first ten of twelve transmembrane segments, with segments 1 - 5 related to 6 - 10 by a pseudo-two-fold axis in the membrane plane. Leucine and the sodium ions are bound within the protein core, halfway across the membrane bilayer, in an occluded site devoid of water. The leucine and ion binding sites are defined by partially unwound transmembrane helices, with main-chain atoms and helix dipoles having key roles in substrate and ion binding. The structure reveals the architecture of this important class of transporter, illuminates the determinants of substrate binding and ion selectivity, and defines the external and internal gates.