mRNA:guanine-N7 cap methyltransferases: identification of novel members of the family, evolutionary analysis, homology modeling, and analysis of sequence-structure-function relationships.
mRNA:guanine-N7 cap methyltransferases: identification of novel members of the family, evolutionary analysis, homology modeling, and analysis of sequence-structure-function relationships.
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DOI：
10.1186/1471-2105-2-2
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发表时间：
2001
影响因子：
3
通讯作者：
Rychlewski L
中科院分区：
文献类型：
--
作者：
Bujnicki JM;Feder M;Radlinska M;Rychlewski L
5'端帽结构在mRNA代谢的许多方面发挥着重要作用。由病毒和病原真菌编码的加帽酶是特定抑制剂的有吸引力的目标。有大量关于进行鸟嘌呤-N7 (cap 0) 甲基化的病毒和细胞甲基转移酶 (MTase) 的实验数据，包括广泛诱变的结果。然而，晶体结构不可用，并且 cap 0 MTase 与已知结构的其他 MTase 差异太大，无法对这些数据进行直接基于同源性的解释。我们报告了 cap 0 MTase 的 3D 模型，该模型是使用序列到结构线程和基于甘氨酸 N-甲基转移酶坐标的比较模型开发的。对 cap 0 MTase 家族系统发育背景中预测的结构特征的分析使我们能够合理化大部分可用的实验数据并提出潜在的结合位点。我们发现了病毒 MTase 辅因子结合位点相关突变的案例，这对于合理的药物设计可能很重要。此外，数据库搜索和系统发育分析揭示了来自植物的假设 MTase 的新亚家族，与“正统”cap 0 MTase 不同。使用计算方法来推断真核帽 MTase 的进化关系并预测其结构。新型帽 MTase 同源物的鉴定为克隆和生化表征提供了候选材料，而结构模型将有助于设计新实验，以更好地了解帽 MTase 的分子功能。
The 5'-terminal cap structure plays an important role in many aspects of mRNA metabolism. Capping enzymes encoded by viruses and pathogenic fungi are attractive targets for specific inhibitors. There is a large body of experimental data on viral and cellular methyltransferases (MTases) that carry out guanine-N7 (cap 0) methylation, including results of extensive mutagenesis. However, a crystal structure is not available and cap 0 MTases are too diverged from other MTases of known structure to allow straightforward homology-based interpretation of these data. We report a 3D model of cap 0 MTase, developed using sequence-to-structure threading and comparative modeling based on coordinates of the glycine N-methyltransferase. Analysis of the predicted structural features in the phylogenetic context of the cap 0 MTase family allows us to rationalize most of the experimental data available and to propose potential binding sites. We identified a case of correlated mutations in the cofactor-binding site of viral MTases that may be important for the rational drug design. Furthermore, database searches and phylogenetic analysis revealed a novel subfamily of hypothetical MTases from plants, distinct from "orthodox" cap 0 MTases. Computational methods were used to infer the evolutionary relationships and predict the structure of Eukaryotic cap MTase. Identification of novel cap MTase homologs suggests candidates for cloning and biochemical characterization, while the structural model will be useful in designing new experiments to better understand the molecular function of cap MTases.
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DOI：
10.1093/bioinformatics/8.3.275
发表时间：
1992-06-01
期刊：
COMPUTER APPLICATIONS IN THE BIOSCIENCES
影响因子：
--
作者：
JONES, DT;TAYLOR, WR;THORNTON, JM
通讯作者：
THORNTON, JM
影响因子：
64.5
作者：
Lima, CD;Wang, LK;Shuman, S
通讯作者：
Shuman, S
影响因子：
5.8
作者：
Cuff, JA;Clamp, ME;Barton, GJ
通讯作者：
Barton, GJ
影响因子：
5.8
作者：
Karplus, K;Barrett, C;Hughey, R
通讯作者：
Hughey, R
影响因子：
5.6
作者：
Jones, DT
通讯作者：
Jones, DT