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Catalysis by the JmjC histone demethylase KDM4A integrates substrate dynamics, correlated motions and molecular orbital control
Chemical Science ( IF 8.4 ) Pub Date : 2020-09-04 , DOI: 10.1039/d0sc03713c
Rajeev Ramanan 1, 2, 3, 4 , Shobhit S. Chaturvedi 1, 2, 3, 4 , Nicolai Lehnert 1, 4, 5, 6 , Christopher J. Schofield 7, 8, 9 , Tatyana G. Karabencheva-Christova 1, 2, 3, 4 , Christo Z. Christov 1, 2, 3, 4
Affiliation  

The Nε-methyl lysine status of histones is important in the regulation of eukaryotic transcription. The Fe(II) and 2-oxoglutarate (2OG) -dependent JmjC domain enzymes are the largest family of histone Nε-methyl lysine demethylases (KDMs). The human KDM4 subfamily of JmjC KDMs is linked with multiple cancers and some of its members are medicinal chemistry targets. We describe the use of combined molecular dynamics (MD) and Quantum Mechanical/Molecular Mechanical (QM/MM) methods to study the mechanism of KDM4A, which catalyzes demethylation of both tri- and di-methylated forms of histone H3 at K9 and K36. The results show that the oxygen activation at the active site of KDM4A is optimized towards the generation of the reactive Fe(IV)-oxo intermediate. Factors including the substrate binding mode, correlated motions of the protein and histone substrates, and molecular orbital control synergistically contribute to the reactivity of the Fe(IV)-oxo intermediate. In silico substitutions were performed to investigate the roles of residues (Lys241, Tyr177, and Asn290) in substrate orientation. The Lys241Ala substitution abolishes activity due to altered substrate orientation consistent with reported experimental studies. Calculations with a macrocyclic peptide substrate analogue reveal that induced conformational changes/correlated motions in KDM4A are sequence-specific in a manner that influences substrate binding affinity. Second sphere residues, such as Ser288 and Thr289, may contribute to KDM4A catalysis by correlated motions with active site residues. Residues that stabilize key intermediates, and which are predicted to be involved in correlated motions with other residues in the second sphere and beyond, are shown to be different in KDM4A compared to those in another JmjC KDM (PHF8), which acts on H3K9 di- and mono-methylated forms, suggesting that allosteric type inhibition is of interest from the perspective of developing selective JmjC KDM inhibitors.

中文翻译:

JmjC组蛋白脱甲基酶KDM4A的催化整合了底物动力学,相关运动和分子轨道控制

所述Ñ ε组蛋白的甲基赖氨酸状态是在真核转录的调节很重要的。中的Fe(II)和2-氧代戊二酸(20克)依赖性JmjC结构域酶的组蛋白的最大家族Ñ ε -甲基赖氨酸脱甲基酶(KDMS)。JmjC KDM的人类KDM4亚家族与多种癌症有关,其某些成员是药物化学靶标。我们描述了结合使用分子动力学(MD)和量子力学/分子力学(QM / MM)方法来研究KDM4A的机理,该机理催化组蛋白H3在K9和K36的三和二甲基化形式的去甲基化。结果表明,在KDM4A的活性位点上的氧活化在反应性Fe(IV)-氧代中间体。包括底物结合模式,蛋白质和组蛋白底物的相关运动以及分子轨道控制在内的因素协同作用有助于Fe(IV)-氧代中间体的反应性。电脑进行取代反应以研究残基(Lys241,Tyr177和Asn290)在底物方向上的作用。与报道的实验研究一致,由于改变的底物方向,Lys241Ala取代废除了活性。用大环肽底物类似物进行的计算表明,KDM4A中诱导的构象变化/相关运动以影响底物结合亲和力的方式是序列特异性的。第二球残基(例如Ser288和Thr289)可能通过与活动位点残基相关的运动来促进KDM4A催化。与其他JmjC KDM(PHF8)相比,在KDM4A中显示出稳定关键中间体的残基被预测与第二个球体及其以外的其他残基相关运动。
更新日期:2020-09-23
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