Exploring the role of active site Mn2+ ions in the binding of protein phosphatase 5 with its substrate using molecular dynamics simulations.
Exploring the role of active site Mn2+ ions in the binding of protein phosphatase 5 with its substrate using molecular dynamics simulations.
复制标题
使用分子动力学模拟探索活性位点 Mn2 离子在蛋白磷酸酶 5 与其底物结合中的作用。
DOI：
10.1016/j.bbrc.2019.02.113
复制
发表时间：
2019
影响因子：
3.1
通讯作者：
Feng Yan
中科院分区：
文献类型：
--
作者：
Lingyun Wang;Feng Yan
蛋白磷酸酶5（PP 5）是丝氨酸/苏氨酸蛋白磷酸酶的重要成员，与多种人类癌症有关。结构数据表明，两个金属离子和两个水分子位于PP 5的活性位点，并参与底物的脱磷酸化。近年来，人们利用密度泛函理论（DFT）研究了PP 5的催化反应，并利用分子动力学（MD）研究了水分子在PP 5底物结合中的作用.这两项研究丰富了我们对PP 5催化机理的认识。然而，金属离子如何调节底物结合以及每个金属离子对催化的贡献的问题仍然没有答案。为此，通过分子动力学模拟研究了催化Mn 2+离子在调节PP 5与其底物结合中的作用。结果表明，不同状态的Mn ~（2+）离子可以改变活性中心的结构以及与Mn ~（2+）离子或底物配位的残基的构象。这导致PP 5的二级结构和动力学波动发生变化，特别是螺旋αJ的二级结构和动力学波动。随着αJ螺旋位置的改变，底物结合口袋的体积随Mn 2+离子状态的不同而改变，表明Mn 2+离子对PP 5活性的调节作用。结合前期的模拟数据，提出了PP 5与底物、两个活性中心水分子和两个Mn ~（2+）离子结合的顺序步骤.这可能有助于开发新的抑制剂来治疗PP 5相关的癌症。
Protein phosphatase 5 (PP5), an important member of serine/threonine protein phosphatases, has been associated with diverse human cancers. Structural data demonstrate that two metal ions and two water molecules are located in the active site of PP5 and are involved in the dephosphorylations of the substrate. Recently, the catalytic reaction of PP5 has been studied by a density functional theory (DFT) method, and the role of the water molecules in regulating the substrate binding of PP5 was explored by our previous molecular dynamics (MD) study. These two studies enrich our understanding of the catalytic mechanism of PP5. However, the questions of how the metal ions regulate the substrate binding and the contribution of each metal ion to the catalysis remain not answered. To this end, the role of the catalytic Mn2+ions in regulating the binding of PP5 with its substrate was investigated through MD simulations. Results reveal that the different states of Mn2+ions can alter the structure of the active site and the conformations of the residues coordinating the Mn2+ions or the substrate. This leads to changes in the secondary structure and dynamical fluctuation of PP5, especially for that of helix αJ. With the position change of helix αJ, the volume of the substrate binding pocket is altered by the different states of Mn2+ions, indicating the regulatory role of Mn2+ions in PP5 activity. Furthermore, combined with the simulation data of our previous study, the sequential steps for PP5 binding of the substrate, the two active site water molecules, and the two Mn2+ions are proposed. This may help to develop new inhibitors to treat the PP5-related cancers.
影响因子：
2.9
作者：
D. J. White;N. J. Reiter;R. Sikkink;L. Yu;F. Rusnak
通讯作者：
D. J. White;N. J. Reiter;R. Sikkink;L. Yu;F. Rusnak
DOI：
10.1124/jpet.109.155630
发表时间：
2009-10-01
影响因子：
3.5
作者：
Swingle, Mark R.;Amable, Lauren;Honkanen, Richard E.
通讯作者：
Honkanen, Richard E.