Department of Chemistry, Michigan Technological University, Houghton, Michigan 49931, USA.
Org Biomol Chem. 2019 Feb 20;17(8):2223-2231. doi: 10.1039/c9ob00162j.
N-Methylation of DNA/RNA bases can be regulatory or damaging and is linked to diseases including cancer and genetic disorders. Bacterial AlkB and human FTO are DNA/RNA demethylases belonging to the Fe(ii) and 2-oxoglutarate oxygenase superfamily. Modelling studies reveal conformational dynamics influence structure-function relationships of AlkB and FTO, e.g. why 1-methyladenine is a better substrate for AlkB than 6-methyladenine. Simulations show that the flexibility of the double stranded DNA substrate in AlkB influences correlated motions, including between the core jelly-roll fold and an active site loop involved in substrate binding. The FTO N- and C-terminal domains move in respect to one another in a manner likely important for substrate binding. Substitutions, including clinically observed ones, influencing catalysis contribute to the network of correlated motions in AlkB and FTO. Overall, the calculations highlight the importance of the overall protein environment and its flexibility to the geometry of the reactant complexes.
DNA/RNA 碱基的 N-甲基化可能具有调节作用或造成损伤，并与癌症和遗传疾病等多种疾病相关。细菌 AlkB 和人类 FTO 是属于 Fe(ii)和 2-氧代戊二酸氧合酶超家族的 DNA/RNA 去甲基酶。模型研究表明构象动力学影响 AlkB 和 FTO 的结构-功能关系，例如为什么 1-甲基腺嘌呤是 AlkB 的比 6-甲基腺嘌呤更好的底物。模拟表明，AlkB 中双链 DNA 底物的柔韧性会影响相关运动，包括核心果冻卷折叠与参与底物结合的活性位点环之间的相关运动。FTO 的 N 端和 C 端结构域相对于彼此移动，这对于底物结合可能很重要。影响催化的突变，包括临床观察到的突变，有助于 AlkB 和 FTO 中相关运动的网络。总体而言，计算结果强调了整体蛋白质环境及其柔韧性对反应复合物几何形状的重要性。
