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首页> 外文期刊>Biochemistry >Structures of Glycosylated Mammalian Glutaminyl Cyclases Reveal Conformational Variability near the Active Center
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Structures of Glycosylated Mammalian Glutaminyl Cyclases Reveal Conformational Variability near the Active Center

机译：糖基化的哺乳动物谷氨酰胺基环化酶的结构揭示了活性中心附近的构象变异性。

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Formation of N-terminal pyroglutamate (pGlu or pE)nfrom glutaminyl or glutamyl precursors is catalyzed by glutaminylncyclases (QC). As the formation of pGlu-amyloid has been linkednwith Alzheimer’s disease, inhibitors of QCs are currently the subjectnof intense development. Here, we report three crystal structures ofnN-glycosylated mammalian QC from humans (hQC) and micen(mQC). Whereas the overall structures of the enzymes are similarnto those reported previously, two surface loops in the neighborhoodnof the active center exhibit conformational variability. Furthermore,ntwo conserved cysteine residues form a disulfide bond at the base ofnthe active center that was not present in previous reports of hQCnstructure. Site-directed mutagenesis suggests a structure-stabilizingnrole of the disulfide bond. At the entrance to the active center, thenconserved tryptophan residue, W207n, which displayed multiple orientations in previous structure, shows a single conformation innboth glycosylated human and murine QCs. Although mutagenesis of W207ninto leucine or glutamine altered substrate conversionnsignificantly, the binding constants of inhibitors such as the highly potent PQ50 (PBD150) were minimally affected. The crystalnstructure of PQ50 bound to the active center ofmurineQC reveals principal binding determinants provided by the catalytic zinc ionnand a hydrophobic funnel. This study presents a first comparison of two mammalian QCs containing typical, conserved post-ntranslational modifications
机译：谷氨酰胺环化酶（QC）催化由谷氨酰胺或谷氨酰胺前体形成N末端焦谷氨酸（pGlu或pE）n。由于pGlu-淀粉样蛋白的形成与阿尔茨海默氏病有关，因此，QCs抑制剂目前正处于强烈发展的主题。在这里，我们报告了人类（hQC）和小鼠（nQC）的nN-糖基化哺乳动物QC的三个晶体结构。尽管酶的总体结构与先前报道的相似，但活性中心附近的两个表面环显示出构象变异性。此外，两个保守的半胱氨酸残基在活性中心的基部形成二硫键，以前的hQCn结构报道中没有。定点诱变表明二硫键具有结构稳定作用。在活性中心的入口处，然后保守的色氨酸残基W207n在以前的结构中显示了多个方向，在糖基化的人和鼠QCs中都显示出一个单一构象。尽管W207nin变为亮氨酸或谷氨酰胺的诱变显着改变了底物转化，但对抑制剂（例如高效PQ50（PBD150））的结合常数的影响却很小。结合到murineQC活性中心的PQ50的晶体结构揭示了催化锌离子和疏水漏斗提供的主要结合决定簇。这项研究首次比较了两种包含典型的，保守的翻译后修饰的哺乳动物质控品

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