Conformational Dynamics Underlies Different Functions of Human KDM7 Histone Demethylases,Chemistry - A European Journal

当前位置： X-MOL 学术 › Chem. Eur. J. › 论文详情

Our official English website, www.x-mol.net, welcomes your feedback! (Note: you will need to create a separate account there.)

Conformational Dynamics Underlies Different Functions of Human KDM7 Histone Demethylases
Chemistry - A European Journal ( IF 3.9 ) Pub Date : 2019-03-26 , DOI: 10.1002/chem.201900492
Shobhit S Chaturvedi ₁ , Rajeev Ramanan ₁ , Sodiq O Waheed ₁ , Jon Ainsley ₂ , Martin Evison ₂ , Jennifer M Ames ₃ , Christopher J Schofield ₄ , Tatyana G Karabencheva-Christova _{1,

2} , Christo Z Christov _{1,

2}

Affiliation

The human KDM7 subfamily histone H3 Nϵ‐methyl lysine demethylases PHF8 (KDM7B) and KIAA1718 (KDM7A) have different substrate selectivities and are linked to genetic diseases and cancer. We describe experimentally based computational studies revealing that flexibility of the region linking the PHD finger and JmjC domains in PHF8 and KIAA1718 regulates interdomain interactions, the nature of correlated motions, and ultimately H3 binding and demethylation site selectivity. F279S an X‐linked mental retardation mutation in PHF8 is involved in correlated motions with the iron ligands and second sphere residues. The calculations reveal key roles of a flexible protein environment in productive formation of enzyme‐substrate complexes and suggest targeting the flexible KDM7 linker region is of interest from a medicinal chemistry perspective.

中文翻译：

构象动力学是人类 KDM7 组蛋白去甲基酶不同功能的基础

人类 KDM7 亚家族组蛋白 H3 N ε -甲基赖氨酸脱甲基酶 PHF8 (KDM7B) 和 KIAA1718 (KDM7A) 具有不同的底物选择性，与遗传性疾病和癌症有关。我们描述了基于实验的计算研究，揭示了 PHF8 和 KIAA1718 中连接 PHD 指和 JmjC 结构域的区域的灵活性调节结构域间相互作用、相关运动的性质以及最终的 H3 结合和去甲基化位点选择性。 F279S 是 PHF8 中的 X 连锁智力迟钝突变，涉及与铁配体和第二球残基的相关运动。这些计算揭示了柔性蛋白质环境在酶-底物复合物的生产形成中的关键作用，并表明从药物化学的角度来看，靶向柔性 KDM7 连接子区域是有意义的。

更新日期：2019-03-26

点击分享查看原文

点击收藏

公开下载

阅读更多本刊新发论文