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首页> 外文期刊>Journal of Molecular Biology >Crystal structures of mammalian glutamine synthetases illustrate substrate-induced conformational changes and provide opportunities for drug and herbicide design
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Crystal structures of mammalian glutamine synthetases illustrate substrate-induced conformational changes and provide opportunities for drug and herbicide design

机译：哺乳动物谷氨酰胺合成物的晶体结构说明了底物诱导的构象变化，并为药物和除草剂设计提供了机会

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摘要

Glutamine synthetase (GS) catalyzes the ligation of glutamate and ammonia to form glutamine, with concomitant hydrolysis of ATR In mammals, the activity eliminates cytotoxic ammonia, at the same time converting neurotoxic glutamate to harmless glutamine; there are a number of links between changes in GS activity and neurodegenerative disorders, such as Alzheimer's disease. In plants, because of its importance in the assimilation and re-assimilation of ammonia, the enzyme is a target of some herbicides. GS is also a central component of bacterial nitrogen metabolism and a potential drug target. Previous studies had investigated the structures of bacterial and plant GSs. In the present publication, we report the first structures of mammalian GSs. The apo form of the canine enzyme was solved by molecular replacement and refined at a resolution of 3 A. Two structures of human glutamine synthetase represent complexes with: a) phosphate, ADP, and manganese, and b) a phosphorylated form of the inhibitor methionine sulfoximine, ADP and manganese; these structures were refined to resolutions of 2.05 angstrom and 2.6 angstrom, respectively. Loop movements near the active site generate more closed forms of the eukaryotic enzymes when substrates are bound; the largest changes are associated with the binding of the nucleotide. Comparisons with earlier structures provide a basis for the design of drugs that are specifically directed at either human or bacterial enzymes. The site of binding the amino acid substrate is highly conserved in bacterial and eukaryotic GSs, whereas the nucleotide binding site varies to a much larger degree. Thus, the latter site offers the best target for specific drug design. Differences between mammalian and plant enzymes are much more subtle, suggesting that herbicides targeting GS must be designed with caution. (c) 2007 Elsevier Ltd. All rights reserved.
机译：谷氨酰胺合成酶（GS）催化谷氨酸和氨的连接形成谷氨酰胺，并伴随ATR水解。在哺乳动物中，该活性消除了细胞毒性氨，同时将神经毒性谷氨酸转化为无害的谷氨酰胺。 GS活动的改变与神经退行性疾病（例如阿尔茨海默氏病）之间存在许多联系。在植物中，由于其在氨的同化和再同化中的重要性，该酶是某些除草剂的目标。 GS也是细菌氮代谢的重要组成部分，也是潜在的药物靶标。先前的研究已经调查了细菌和植物GS的结构。在本出版物中，我们报告了哺乳动物GS的第一个结构。犬酶的脱辅基形式通过分子置换来解决，并以3 A的分辨率进行精制。人谷氨酰胺合成酶的两个结构代表与以下化合物的复合物：a）磷酸盐，ADP和锰，以及b）蛋氨酸抑制剂的磷酸化形式亚砜亚胺，ADP和锰;这些结构分别被精炼为2.05埃和2.6埃的分辨率。当结合底物时，在活性位点附近的环运动产生了更封闭的真核酶形式。最大的变化与核苷酸的结合有关。与早期结构的比较为设计专门针对人或细菌酶的药物提供了基础。结合氨基酸底物的位点在细菌和真核GS中高度保守，而核苷酸结合位点的变化程度更大。因此，后一个站点为特定药物设计提供了最佳目标。哺乳动物和植物酶之间的差异要细微得多，这表明针对GS的除草剂必须谨慎设计。 （c）2007 Elsevier Ltd.保留所有权利。

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