Structure of human O-GlcNAc transferase and its complex with a peptide substrate.
Structure of human O-GlcNAc transferase and its complex with a peptide substrate.
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DOI：
10.1038/nature09638
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发表时间：
2011-01-27
期刊：
影响因子：
64.8
通讯作者：
Walker, Suzanne
中科院分区：
文献类型：
--
作者：
Lazarus, Michael B.;Nam, Yunsun;Jiang, Jiaoyang;Sliz, Piotr;Walker, Suzanne
O-GlcNAc转移酶（OGT）是一种重要的哺乳动物酶，通过充当营养传感器将代谢状态与多种细胞信号传导途径的调节偶联。OGT催化N-乙酰葡糖胺从UDP-GlcNAc转移至细胞质、细胞核和线粒体蛋白的丝氨酸和苏氨酸，包括许多转录因子、肿瘤抑制因子、激酶、磷酸酶和组蛋白修饰蛋白。OGT引起的O-GlcNAc酰化异常与胰岛素抵抗、糖尿病并发症、癌症和包括阿尔茨海默氏症在内的神经退行性疾病有关。尽管OGT的重要性，它如何识别和糖基化其蛋白质底物的细节在很大程度上是未知的。我们在这里报告两个晶体结构的人OGT，作为一个二元复合物与UDP（2.8 A）和三元复合物与UDP和肽底物（1.95 A）。这些结构提供了酶机制的线索，显示了OGT如何识别靶肽序列，并揭示了催化区两半之间的独特结构域的折叠。这些信息将加速生物实验的合理设计，以研究OGT的功能和设计用作细胞探针的抑制剂，并评估其作为治疗靶点的潜力。
O-GlcNAc transferase (OGT) is an essential mammalian enzyme that couples metabolic status to the regulation of a wide variety of cellular signaling pathways by acting as a nutrient sensor. OGT catalyzes the transfer of N-acetyl-glucosamine from UDP-GlcNAc to serines and threonines of cytoplasmic, nuclear and mitochondrial proteins, including numerous transcription factors, tumor suppressors, kinases, phosphatases, and histone-modifying proteins. Aberrant O-GlcNAcylation by OGT has been linked to insulin resistance, diabetic complications, cancer and neurodegenerative diseases including Alzheimer’s. Despite the importance of OGT, the details of how it recognizes and glycosylates its protein substrates are largely unknown. We report here two crystal structures of human OGT, as a binary complex with UDP (2.8 A) and a ternary complex with UDP and a peptide substrate (1.95 A). The structures provide clues to the enzyme mechanism, show how OGT recognizes target peptide sequences, and reveal the fold of the unique domain between the two halves of the catalytic region. This information will accelerate the rational design of biological experiments to investigate OGT’s functions and the design of inhibitors for use as cellular probes and to assess its potential as a therapeutic target.
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DOI：
10.1107/s0907444905036693
发表时间：
2006-01-01
影响因子：
2.2
作者：
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通讯作者：
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DOI：
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发表时间：
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影响因子：
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Fantus, IG
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通讯作者：
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