Structural basis for synthesis of inflammatory mediators by human leukotriene C4 synthase
Structural basis for synthesis of inflammatory mediators by human leukotriene C4 synthase
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DOI：
10.1038/nature06009
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发表时间：
2007-08-02
期刊：
影响因子：
64.8
通讯作者：
Nordlund, Paer
中科院分区：
文献类型：
--
作者：
Molina, Daniel Martinez;Wetterholm, Anders;Nordlund, Paer
半胱氨酰白三烯是炎症中的关键介质，并且在心血管和呼吸系统的急性和慢性炎性疾病，特别是支气管哮喘中具有重要作用。在半胱氨酰白三烯的生物合成中，花生四烯酸的转化形成不稳定的环氧化物白三烯A（4）（LTA（4））。该中间体与谷胱甘肽（GSH）结合，在LTC 4合酶催化的反应中产生白三烯C-4（LTC 4）（1）：该反应是半胱氨酰白三烯形成的关键步骤。在这里，我们提出的晶体结构的人LTC 4合酶在其载脂蛋白和谷胱甘肽复合形式，以2.00和2.15埃分辨率分别。结构揭示了同源三聚体，其中每个单体由四个跨膜区段组成。与底物复合的酶的结构表明，活性位点在GSH上形成马蹄形构象，并有效地定位巯基，以便在膜-酶界面处被附近的精氨酸激活。此外，该结构提供了一个模型，说明亲脂性共底物的ω-端如何固定在疏水裂缝的一端，提供了一个分子“标尺”，使反应性环氧化物与谷胱甘肽的硫醇对齐.这为LTC 4形成机制提供了新的结构见解，也表明观察到的GSH结合和激活可能是炎症和解毒反应重要的同源蛋白家族的共同点。
Cysteinyl leukotrienes are key mediators in inflammation and have an important role in acute and chronic inflammatory diseases of the cardiovascular and respiratory systems, in particular bronchial asthma. In the biosynthesis of cysteinyl leukotrienes, conversion of arachidonic acid forms the unstable epoxide leukotriene A(4) (LTA(4)). This intermediate is conjugated with glutathione (GSH) to produce leukotriene C-4 (LTC4) in a reaction catalysed by LTC4 synthase(1): this reaction is the key step in cysteinyl leukotriene formation. Here we present the crystal structure of the human LTC4 synthase in its apo and GSH- complexed forms to 2.00 and 2.15 angstrom resolution, respectively. The structure reveals a homotrimer, where each monomer is composed of four transmembrane segments. The structure of the enzyme in complex with substrate reveals that the active site enforces a horseshoe- shaped conformation on GSH, and effectively positions the thiol group for activation by a nearby arginine at the membrane - enzyme interface. In addition, the structure provides a model for how the omega- end of the lipophilic co- substrate is pinned at one end of a hydrophobic cleft, providing a molecular 'ruler' to align the reactive epoxide at the thiol of glutathione. This provides newstructural insights into themechanismof LTC4 formation, and also suggests that the observed binding and activation of GSHmight be common for a family of homologous proteins important for inflammatory and detoxification responses.