Devadas Sudheesh, Thomas Midhun George, Rifayee Simahudeen Bathir Jaber Sathik, Varada Bhargav, White Walter, Sommer Ethan, Campbell Kylin, Schofield Christopher J, Christov Christo Z
Department of Chemistry, Michigan Technological University, Houghton, MI-49931, United States.
Department of Biomedical Engineering, Michigan Technological University, Houghton, MI-49931, United States.
Chemistry. 2025 Jan 14;31(3):e202403989. doi: 10.1002/chem.202403989. Epub 2024 Nov 18.
Histone lysine demethylase 4 A (KDM4A), a non-heme Fe(II)/2-oxoglutarate (2OG) dependent oxygenase that catalyzes the demethylation of tri-methylated lysine residues at the 9, 27, and 36 positions of histone H3 (H3 K9me3, H3 K27me3, and H3 K36me3). These methylated residues show contrasting transcriptional roles; therefore, understanding KDM4A's catalytic mechanisms with these substrates is essential to explain the factors that control the different sequence-dependent demethylations. In this study, we use molecular dynamics (MD)-based combined quantum mechanics/molecular mechanics (QM/MM) methods to investigate determinants of KDM4A catalysis with H3 K9me3, H3 K27me3 and H3 K36me3 substrates. In KDM4A-H3K9me3 and KDM4A-H3K27me3 ferryl complexes, the O-H distance positively correlates with the activation barrier of the rate-limiting step, however in the KDM4A-H3K36me3, no direct one-to-one relationship was found implying that the synergistic effects between the geometric parameters, second sphere interactions and the intrinsic electric field contribute for the effective catalysis for this substrate. The intrinsic electric field along the Fe-O bond changes between the three complexes and shows a positive correlation with the HAT activation barrier, suggesting that modulating electric field can be used for fine engineering KDM catalysis with a specific substrate. The results reveal how KDM4A uses a combination of strategies to enable near equally efficient demethylation of different H3Kme3 residues.
组蛋白赖氨酸去甲基化酶4A（KDM4A）是一种非血红素铁（II）/2-氧代戊二酸（2OG）依赖性加氧酶，可催化组蛋白H3第9、27和36位三甲基化赖氨酸残基的去甲基化（H3 K9me3、H3 K27me3和H3 K36me3）。这些甲基化残基表现出相反的转录作用；因此，了解KDM4A与这些底物的催化机制对于解释控制不同序列依赖性去甲基化的因素至关重要。在本研究中，我们使用基于分子动力学（MD）的组合量子力学/分子力学（QM/MM）方法来研究KDM4A催化H3 K9me3、H3 K27me3和H3 K36me3底物的决定因素。在KDM4A-H3K9me3和KDM4A-H3K27me3高铁络合物中，O-H距离与限速步骤的活化能垒呈正相关，然而在KDM4A-H3K36me3中，未发现直接的一一对应关系，这意味着几何参数、第二配位层相互作用和固有电场之间的协同作用有助于该底物的有效催化。三种络合物之间沿Fe-O键的固有电场发生变化，并与HAT活化能垒呈正相关，这表明调节电场可用于对特定底物的KDM催化进行精细调控。结果揭示了KDM4A如何使用多种策略实现不同H3Kme3残基几乎同等高效的去甲基化。
