Defining the structural origin of the substrate sequence independence of O-GlcNAcase using a combination of molecular docking and dynamics simulation.
Defining the structural origin of the substrate sequence independence of O-GlcNAcase using a combination of molecular docking and dynamics simulation.
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DOI：
10.1093/glycob/cwt094
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发表时间：
2014-01
期刊：
影响因子：
4.3
通讯作者：
Woods RJ
中科院分区：
文献类型：
--
作者：
Martin JC;Fadda E;Ito K;Woods RJ
O-linked N-acetylglucosamine （O-GlcNAc）的蛋白糖基化是核细胞质蛋白中丝氨酸/苏氨酸残基的翻译后修饰。O-GlcNAc已被证明在许多不同的细胞过程中发挥作用，并且O-GlcNAc酰化通常在已知的磷酸化位点上发现。与磷酸化不同，O-GlcNAc水平仅受两种酶的调节，即O-GlcNAc转移酶（OGT）和O-GlcNAc水解酶（O-GlcNAcase或OGA）。到目前为止，对于o - glcnac酰化位点还没有找到明显的一致序列。此外，O-GlcNAcase可以识别和切割所有的o - glcn酰化蛋白，而不依赖于它们的序列。在这项工作中，我们生成并分析了五种与细菌OGA复合物的o - glcn酰化肽模型。五种糖肽中的每一种都以类似的方式与OGA结合，OGA与肽的相互作用主要涉及肽主链原子，但不是唯一的，因此解释了对肽序列缺乏敏感性。尽管如此，肽序列的差异，特别是在−1到−4位置，导致预测亲和力的变化，与酶动力学中观察到的实验变化一致。因此，利用目前的分析来指导糖肽特异性抑制剂的开发，或者反过来，将OGA转化为一种可以靶向特定o - glcn酰化肽序列的试剂，是有潜力的。
Protein glycosylation with O-linked N-acetylglucosamine (O-GlcNAc) is a post-translational modification of serine/threonine residues in nucleocytoplasmic proteins. O-GlcNAc has been shown to play a role in many different cellular processes and O-GlcNAcylation is often found at sites that are also known to be phosphorylated. Unlike phosphorylation, O-GlcNAc levels are regulated by only two enzymes, O-GlcNAc transferase (OGT) and O-GlcNAc hydrolase (O-GlcNAcase or OGA). So far, no obvious consensus sequence has been found for sites of O-GlcNAcylation. Additionally, O-GlcNAcase recognizes and cleaves all O-GlcNAcylated proteins, independent of their sequence. In this work, we generate and analyze five models of O-GlcNAcylated peptides in complex with a bacterial OGA. Each of the five glycopeptides bind to OGA in a similar fashion, with OGA–peptide interactions primarily, but not exclusively, involving the peptide backbone atoms, thus explaining the lack of sensitivity to peptide sequence. Nonetheless, differences in peptide sequences, particularly at the −1 to −4 positions, lead to variations in predicted affinity, consistent with observed experimental variations in enzyme kinetics. The potential exists, therefore, to employ the present analysis to guide the development glycopeptide-specific inhibitors, or conversely, the conversion of OGA into a reagent that could target specific O-GlcNAcylated peptide sequences.
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影响因子：
56.9
作者：
CHO, YJ;GORINA, S;PAVLETICH, NP
通讯作者：
PAVLETICH, NP
影响因子：
5.5
作者：
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DOI：
10.1073/pnas.0602815103
发表时间：
2006-05-23
影响因子：
11.1
作者：
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通讯作者：
Woods, Robert J.
影响因子：
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作者：
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通讯作者：
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