Bishop T C, Schulten K
Beckman Institute, Department of Chemistry, University of Illinois at Urbana-Champaign 61801, USA.
Proteins. 1996 Jan;24(1):115-33. doi: 10.1002/(SICI)1097-0134(199601)24:1<115::AID-PROT8>3.0.CO;2-J.
Molecular dynamics simulations have been conducted to investigate the binding of the glucocorticoid receptor (GR) dimer to DNA. For this purpose simulations of the complex formed by a DNA segment and a dimer of GR-DNA binding domains (GR-DBD) have been carried out, employing an available X-ray structure. A second set of simulations was based on this structure as well, except that the DNA segment was altered to the consensus glucocorticoid response element (GRE). Simulations of a single GR-DBD and of the uncomplexed GRE served as controls. For the simulations, each system was encapsulated in an ellipsoid of water. Protein-DNA interactions, dimer interactions, and DNA structural parameters were analyzed for each system and compared. The consensus GRE is found to yield more favorable and symmetric interactions between the GR-DBDs and the GRE, explaining the ability of the GR dimer to recognize this DNA segment. Further analysis focused on deformations of the DNA that are induced by the binding of GR. The deformations observed involve a 35 degree bend of the DNA, an unwinding, and a displacement of the helical axis. These deformations are consistent with a mechanism for transcriptional regulation that involves a change of nucleosome packing upon GR binding. Significant protein-protein and protein-DNA interactions, both direct and water mediated, develop due to the deformations of the GRE and are indicative of an increased recognition achieved through DNA deformation. The interactions include direct interactions between the GRE and glycine-458 and serine-459, side groups which differentiate GR from other members of the nuclear hormone receptor family.
已进行分子动力学模拟以研究糖皮质激素受体（GR）二聚体与DNA的结合。为此，利用现有的X射线结构，对由一段DNA和GR-DNA结合域（GR-DBD）二聚体形成的复合物进行了模拟。第二组模拟也是基于该结构进行的，只是将DNA片段改为共有糖皮质激素反应元件（GRE）。对单个GR-DBD和未复合的GRE进行模拟作为对照。对于模拟，每个系统都封装在一个水椭球中。分析并比较了每个系统的蛋白质-DNA相互作用、二聚体相互作用和DNA结构参数。发现共有GRE在GR-DBD与GRE之间产生更有利且对称的相互作用，这解释了GR二聚体识别该DNA片段的能力。进一步的分析集中在GR结合诱导的DNA变形上。观察到的变形包括DNA的35度弯曲、解旋以及螺旋轴的位移。这些变形与一种转录调控机制一致，该机制涉及GR结合后核小体堆积的变化。由于GRE的变形，会产生显著的蛋白质-蛋白质和蛋白质-DNA相互作用，包括直接相互作用和水介导的相互作用，这表明通过DNA变形实现了更高的识别度。这些相互作用包括GRE与甘氨酸-458和丝氨酸-459之间的直接相互作用，这些侧链基团使GR区别于核激素受体家族的其他成员。
