Mechanism of the Conformational Change of the Protein Methyltransferase SMYD3: A Molecular Dynamics Simulation Study.
Mechanism of the Conformational Change of the Protein Methyltransferase SMYD3: A Molecular Dynamics Simulation Study.
复制标题
蛋白质甲基转移酶SMYD3构象变化机制：分子动力学模拟研究
DOI：
10.3390/ijms22137185
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发表时间：
2021-07-02
影响因子：
5.6
通讯作者：
Yang N
中科院分区：
文献类型：
--
作者：
Sun J;Li Z;Yang N
SMYD 3是一种含有SET结构域的甲基转移酶，催化甲基转移到底物蛋白的赖氨酸残基上。MAP 3 K2被SMYD 3甲基化与Ras驱动的肿瘤发生有关，这使得SMYD 3成为癌症治疗的潜在靶点。在所有SMYD家族蛋白中，SMYD 3在晶体结构中采用闭合构象。一些研究表明，开放和封闭形式之间的构象变化可能会调节SMYD 3的催化活性。在这项工作中，我们进行了广泛的分子动力学模拟的一系列复合物，共21 μs的采样，研究的构象变化的SMYD 3和揭示的分子机制。基于C-末端结构域的运动，模拟模型可以被描述为三种不同的构象状态：封闭，中间和开放状态。只有在甲基供体结合口袋和靶赖氨酸结合通道都具有结合物质的情况下，模拟才显示SMYD 3在闭合状态下保持其构象，表明辅因子和靶赖氨酸对调节SMYD 3构象变化的协同作用。此外，我们在结构和能量方面进行了分析，以阐明这两个区域如何调节C-末端结构域的运动。这一机制的研究提供了深入了解SMYD 3的构象变化和甲基转移酶活性之间的关系。更完整的了解构象动力学的发展与进一步的工作一起，可能奠定了合理的药物设计的SMYD 3抑制剂的基础。
SMYD3 is a SET-domain-containing methyltransferase that catalyzes the transfer of methyl groups onto lysine residues of substrate proteins. Methylation of MAP3K2 by SMYD3 has been implicated in Ras-driven tumorigenesis, which makes SMYD3 a potential target for cancer therapy. Of all SMYD family proteins, SMYD3 adopt a closed conformation in a crystal structure. Several studies have suggested that the conformational changes between the open and closed forms may regulate the catalytic activity of SMYD3. In this work, we carried out extensive molecular dynamics simulations on a series of complexes with a total of 21 μs sampling to investigate the conformational changes of SMYD3 and unveil the molecular mechanisms. Based on the C-terminal domain movements, the simulated models could be depicted in three different conformational states: the closed, intermediate and open states. Only in the case that both the methyl donor binding pocket and the target lysine-binding channel had bound species did the simulations show SMYD3 maintaining its conformation in the closed state, indicative of a synergetic effect of the cofactors and target lysine on regulating the conformational change of SMYD3. In addition, we performed analyses in terms of structure and energy to shed light on how the two regions might regulate the C-terminal domain movement. This mechanistic study provided insights into the relationship between the conformational change and the methyltransferase activity of SMYD3. The more complete understanding of the conformational dynamics developed here together with further work may lay a foundation for the rational drug design of SMYD3 inhibitors.
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影响因子：
1.5
作者：
Spellmon N;Sun X;Xue W;Holcomb J;Chakravarthy S;Shang W;Edwards B;Sirinupong N;Li C;Yang Z
通讯作者：
Yang Z
影响因子：
4
作者：
Colon-Bolea, Paula;Crespo, Piero
通讯作者：
Crespo, Piero
DOI：
10.1016/j.bbagen.2016.04.006
发表时间：
2016-07-01
影响因子：
3
作者：
Chandramouli, Balasubramanian;Silvestri, Valentina;Chillemi, Giovanni
通讯作者：
Chillemi, Giovanni
影响因子：
4.4
作者：
JORGENSEN, WL;CHANDRASEKHAR, J;KLEIN, ML
通讯作者：
KLEIN, ML
DOI：
10.1073/pnas.202427399
发表时间：
2002-10-01
影响因子：
11.1
作者：
Laio, A;Parrinello, M
通讯作者：
Parrinello, M