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首页> 外文期刊>Journal of Molecular Biology >Structure-Based Insights into the Role of the Cys-Tyr Crosslink and Inhibitor Recognition by Mammalian Cysteine Dioxygenase
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Structure-Based Insights into the Role of the Cys-Tyr Crosslink and Inhibitor Recognition by Mammalian Cysteine Dioxygenase

机译：基于结构的见解对哺乳动物半胱氨酸双加氧酶的Cys-Tyr交联和抑制剂识别的作用

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摘要

In mammals, the non-heme iron enzyme cysteine dioxygenase (CDO) helps regulate Cys levels through converting Cys to Cys sulfinic acid. Its activity is in part modulated by the formation of a Cys93-Tyr157 crosslink that increases its catalytic efficiency over 10-fold. Here, 21 high-resolution mammalian CDO structures are used to gain insight into how the Cys-Tyr crosslink promotes activity and how select competitive inhibitors bind. Crystal structures of crosslink-deficient C93A and Y157F variants reveal similar similar to 1.0-A shifts in the side chain of residue 157, and both variant structures have a new chloride ion coordinating the active site iron. Cys binding is also different from wild-type CDO, and no Cys-persulfenate forms in the C93A or Y157F active sites at pH 6.2 or 8.0. We conclude that the crosslink enhances activity by positioning the Tyr157 hydroxyl to enable proper Cys binding, proper oxygen binding, and optimal chemistry. In addition, structures are presented for homocysteine (Hcy), D-Cys, thiosulfate, and azide bound as competitive inhibitors. The observed binding modes of Hcy and D-Cys clarify why they are not substrates, and the binding of azide shows that in contrast to what has been proposed, it does not bind in these crystals as a superoxide mimic. (C) 2016 Elsevier Ltd. All rights reserved.
机译：在哺乳动物中，非血红素铁酶半胱氨酸双加氧酶（CDO）通过将Cys转化为Cys亚磺酸来帮助调节Cys的水平。 Cys93-Tyr157交联的形成可部分调节其活性，该交联可将其催化效率提高10倍以上。在这里，使用21种高分辨率哺乳动物CDO结构来深入了解Cys-Tyr交联如何促进活性以及选择的竞争性抑制剂如何结合。交联缺陷的C93A和Y157F变体的晶体结构显示出与残基157侧链的1.0-A位移相似，并且两个变体结构都有一个新的氯离子与活性位铁配位。 Cys的结合也不同于野生型CDO，并且在pH 6.2或8.0的C93A或Y157F活性位中没有Cys-过亚磺酸盐形式。我们得出的结论是，交联通过定位Tyr157羟基来增强活性，以使适当的Cys结合，适当的氧结合和最佳化学反应成为可能。此外，还提出了高半胱氨酸（Hcy），D-Cys，硫代硫酸盐和叠氮化物作为竞争性抑制剂的结构。观察到的Hcy和D-Cys的结合模式阐明了为什么它们不是底物，而叠氮化物的结合表明与所提出的相反，它不作为超氧化物模拟物结合在这些晶体中。 （C）2016 Elsevier Ltd.保留所有权利。

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