Department of Mathematics and Computer Science, Freie Universität Berlin, 14195 Berlin, Germany.
Computational Molecular Design, Pharmaceuticals, R&D, Bayer AG, 42096 Wuppertal, Germany.
Proc Natl Acad Sci U S A. 2021 Jan 26;118(4). doi: 10.1073/pnas.2017427118.
Bromodomains (BDs) are small protein modules that interact with acetylated marks in histones. These posttranslational modifications are pivotal to regulate gene expression, making BDs promising targets to treat several diseases. While the general structure of BDs is well known, their dynamical features and their interplay with other macromolecules are poorly understood, hampering the rational design of potent and selective inhibitors. Here, we combine extensive molecular dynamics simulations, Markov state modeling, and available structural data to reveal a transiently formed state that is conserved across all BD families. It involves the breaking of two backbone hydrogen bonds that anchor the ZA-loop with the α helix, opening a cryptic pocket that partially occludes the one associated to histone binding. By analyzing more than 1,900 experimental structures, we unveil just two adopting the hidden state, explaining why it has been previously unnoticed and providing direct structural evidence for its existence. Our results suggest that this state is an allosteric regulatory switch for BDs, potentially related to a recently unveiled BD-DNA-binding mode.
溴结构域（BDs）是与组蛋白中乙酰化标记相互作用的小蛋白模块。这些翻译后修饰对于调节基因表达至关重要，使得 BDs 成为治疗多种疾病的有前途的靶点。虽然 BDs 的一般结构是众所周知的，但它们的动力学特征及其与其他大分子的相互作用仍知之甚少，这阻碍了有效和选择性抑制剂的合理设计。在这里，我们结合广泛的分子动力学模拟、马尔可夫状态建模和可用的结构数据，揭示了一种在所有 BD 家族中都保守的瞬时形成状态。它涉及到破坏两个将 ZA 环与 α 螺旋连接的骨干氢键，打开一个隐藏的口袋，部分遮挡与组蛋白结合相关的口袋。通过分析超过 1900 个实验结构，我们揭示了只有两种结构采用隐藏状态，这解释了为什么之前没有注意到它，并为其存在提供了直接的结构证据。我们的结果表明，这种状态是 BDs 的变构调节开关，可能与最近发现的 BD-DNA 结合模式有关。
