The dynamic conformational landscape of the protein methyltransferase SETD8
The dynamic conformational landscape of the protein methyltransferase SETD8
复制标题
蛋白质甲基转移酶 SETD8 的动态构象景观
DOI：
10.7554/elife.45403
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发表时间：
2019-05-13
期刊：
影响因子：
7.7
通讯作者：
Luo, Minkui
中科院分区：
文献类型：
--
作者：
Chen, Shi;Wiewiora, Rafal P.;Luo, Minkui
阐明蛋白质的构象异质性对于理解蛋白质的功能和开发外源配体是必不可少的。随着实验和计算方法的快速发展，将这些方法结合在一起来阐明目标蛋白质的构象景观是非常有意义的。SETD8是一种蛋白质赖氨酸甲基转移酶(PKMT)，在体内通过组蛋白和非组蛋白靶标的甲基化发挥作用。利用共价抑制剂和耗尽天然配体来捕获隐藏的构象状态，我们得到了SETD8的各种X射线结构。这些结构被用于生成总共6毫秒的轨迹数据的分布式原子分子动力学模拟。马尔可夫状态模型是通过自动机器学习方法建立的，并得到了实验的证实，揭示了缓慢的构象运动和构象状态与催化有关。这些发现通过PKMT的详细构象提供了对其酶催化和变构机制的分子洞察力。
Elucidating the conformational heterogeneity of proteins is essential for understanding protein function and developing exogenous ligands. With the rapid development of experimental and computational methods, it is of great interest to integrate these approaches to illuminate the conformational landscapes of target proteins. SETD8 is a protein lysine methyltransferase (PKMT), which functions in vivo via the methylation of histone and nonhistone targets. Utilizing covalent inhibitors and depleting native ligands to trap hidden conformational states, we obtained diverse X-ray structures of SETD8. These structures were used to seed distributed atomistic molecular dynamics simulations that generated a total of six milliseconds of trajectory data. Markov state models, built via an automated machine learning approach and corroborated experimentally, reveal how slow conformational motions and conformational states are relevant to catalysis. These findings provide molecular insight on enzymatic catalysis and allosteric mechanisms of a PKMT via its detailed conformational landscape.