X-ray structures of GluCl in apo states reveal a gating mechanism of Cys-loop receptors.
X-ray structures of GluCl in apo states reveal a gating mechanism of Cys-loop receptors.
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DOI：
10.1038/nature13669
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发表时间：
2014-08-21
期刊：
影响因子：
64.8
通讯作者：
Gouaux, Eric
中科院分区：
文献类型：
--
作者：
Althoff, Thorsten;Hibbs, Ryan E.;Banerjee, Surajit;Gouaux, Eric
Cys-loop受体是一种神经递质门控离子通道，是快速化学神经传递的重要介质，与大量神经系统疾病和寄生虫感染有关。这个离子通道超家族的成员根据它们的配体和离子选择性来调节兴奋性或抑制性神经传递。Cys-loop受体的结构信息来源于多种来源，包括烟碱型乙酰胆碱受体的电子显微镜研究、胞外区的高分辨率X射线结构和细菌直系物的X射线结构。2011年，我们的团队发表了秀丽线虫谷氨酸门控氯通道(GluCl)与变构部分激动剂伊维菌素的复合体的结构，这为我们深入了解了真核细胞环状受体可能开放状态的结构，阴离子选择性和通道阻断的基础，以及伊维菌素和相关分子稳定开放状态和增强神经递质结合的机制。然而，关于通道开放和关闭的机制，关闭离子通道门的位置和性质，关闭/静止、开放/激活和关闭/不敏感状态之间的转换，以及细胞外正构体激动剂结合结构域和跨膜离子通道结构域之间的构象变化耦合的机制，仍然没有答案。在这里，我们提出了在没有伊维菌素的情况下GluCl的两种不同的构象结构。结构比较揭示了细胞外域和跨膜域之间的刚体运动引起的第四级激活机制，以及磷脂对受体的调节机制。
Cys-loop receptors are neurotransmitter-gated ion channels that are essential mediators of fast chemical neurotransmission and are associated with a large number of neurological diseases and disorders, as well as parasitic infections. Members of this ion channel superfamily mediate excitatory or inhibitory neurotransmission depending on their ligand and ion selectivity. Structural information for Cys-loop receptors comes from several sources including electron microscopic studies of the nicotinic acetylcholine receptor , high resolution x-ray structures of extracellular domains and x-ray structures of bacterial orthologs . In 2011 our group published structures of the Caenorhabditis elegans glutamate-gated chloride channel (GluCl) in complex with the allosteric partial agonist, ivermectin, which provided insights into the structure of a possibly open state of a eukaryotic Cys-loop receptor, the basis for anion selectivity and channel block, and the mechanism by which ivermectin and related molecules stabilize the open state and potentiate neurotransmitter binding. However, there remain unanswered questions about the mechanism of channel opening and closing, the location and nature of the shut ion channel gate, the transitions between the closed/resting, open/activated and closed/desensitized states, and the mechanism by which conformational changes are coupled between the extracellular, orthosteric agonist binding domain and the transmembrane, ion channel domain. Here we present two conformationally distinct structures of GluCl in the absence of ivermectin. Structural comparisons reveal a quaternary activation mechanism arising from rigid body movements between the extracellular and transmembrane domains and a mechanism for modulation of the receptor by phospholipids.
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影响因子：
3.8
作者：
Lee, Won Yong;Free, Chris R.;Sine, Steven M.
通讯作者：
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DOI：
10.1107/s0907444904019158
发表时间：
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作者：
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DOI：
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发表时间：
2007-02
期刊：
The Journal of general physiology
影响因子：
--
作者：
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通讯作者：
Akabas MH