Ab initio fragment molecular orbital study of molecular interactions between liganded retinoid x receptor and its coactivator: Roles of helix 12 in the coactivator binding mechanism
Ab initio fragment molecular orbital study of molecular interactions between liganded retinoid x receptor and its coactivator: Roles of helix 12 in the coactivator binding mechanism
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DOI：
10.1021/jp070054w
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发表时间：
2007-04-07
影响因子：
3.3
通讯作者：
Tanaka, Shigenori
中科院分区：
文献类型：
--
作者：
Ito, Mika;Fukuzawa, Kaori;Tanaka, Shigenori
在片段分子轨道方法的基础上，我们研究了配体维甲酸X受体（RXR）与类固醇受体共激活因子-1（SRC 1）共激活因子的分子相互作用，以研究包含转录激活功能2激活结构域核心的螺旋12（H12）对RXR共激活因子结合的贡献。H12和SRC 1之间的相互作用被证明是稳定辅激活因子结合的主要原因。特别是，H12中高度保守的带电残基（Glu 453）和疏水残基（Phe 450）被发现与SRC 1具有比H12中的其他带电残基和疏水残基更强的静电和分散相互作用。此外，发现从RXR到SRC 1的电荷转移（CT）主要通过H12残基的电荷变化发生。在SRC 1中分别观察到Glu 453和Lys 631和Ile 632的大的正电荷和负电荷变化，表明Glu 453是该CT中Lys 631和Ile 632的电子供体。两者合计，我们的研究结果定量地表明，H12及其高度保守的残基显着有助于辅激活剂结合，不仅通过库仑和色散相互作用，而且通过与量子力学框架所描述的CT。
On the basis of the fragment molecular orbital method we addressed molecular interactions of liganded retinoid X receptor (RXR) with steroid receptor co-activating factor-1 (SRC1) coactivator to examine the contribution of helix 12 (H12), which contains the core of the transcriptional activation function 2 activating domain, to the coactivator binding of RXR. The interaction between H12 and SRC1 was proved to be the main cause for the stabilization of the coactivator binding. In particular, highly conserved charged (Glu453) and hydrophobic (Phe450) residues in H12 were found to have stronger electrostatic and dispersion interactions with SRC1 than the other charged and hydrophobic residues in H12, respectively. In addition, the charge transfer (CT) from RXR to SRC1 was found to occur mainly by the changes in charges of H12 residues. Large positive and negative charge changes were observed especially for Glu453 and for Lys631 and Ile632 in SRC1, respectively, indicating that Glu453 is an electron donor for Lys631 and Ile632 in this CT. Taken together, our findings quantitatively demonstrated that H12 and its highly conserved residues significantly contribute to the coactivator binding not only by the Coulomb and dispersion interactions but also by the CT described with the quantum-mechanical framework.