Department of Chemistry, Pennsylvania State University, University Park, Pennsylvania 16802, USA.
Department of Biochemistry and Molecular Biology, Pennsylvania State University, University Park, Pennsylvania 16802, USA.
J Chem Phys. 2024 Mar 21;160(11). doi: 10.1063/5.0189234.
Nuclear receptors regulate transcriptional programs in response to the binding of natural and synthetic ligands. These ligands modulate the receptor by inducing dynamic changes in the ligand binding domain that shift the C-terminal helix (H12) between active and inactive conformations. Despite decades of study, many questions persist regarding the nature of the inactive state and how ligands shift receptors between different states. Here, we use molecular dynamics (MD) simulations to investigate the timescale and energetic landscape of the conformational transition between inactive and active forms of progesterone receptor (PR) bound to a partial agonist. We observe that the microsecond timescale is insufficient to observe any transitions; only at millisecond timescales achieved via accelerated MD simulations do we find the inactive PR switches to the active state. Energetic analysis reveals that both active and inactive PR states represent energy minima separated by a barrier that can be traversed. In contrast, little or no transition is observed between active and inactive states when an agonist or antagonist is bound, confirming that ligand identity plays a key role in defining the energy landscape of nuclear receptor conformations.
核受体通过结合天然和合成配体来调节转录程序。这些配体通过诱导配体结合域的动态变化来调节受体，从而将 C 端螺旋（H12）在活性和非活性构象之间移动。尽管已经进行了几十年的研究，但关于非活性状态的本质以及配体如何在不同状态之间转换受体，仍有许多问题存在。在这里，我们使用分子动力学（MD）模拟来研究孕激素受体（PR）与部分激动剂结合的非活性和活性形式之间构象转变的时间尺度和能量景观。我们观察到微秒时间尺度不足以观察到任何转变；只有在毫秒时间尺度下，通过加速 MD 模拟，我们才发现非活性 PR 切换到活性状态。能量分析表明，活性和非活性 PR 状态都代表了由能垒分隔的能量最小值，而该能垒可以被跨越。相比之下，当结合激动剂或拮抗剂时，在活性和非活性状态之间几乎观察不到转变，这证实了配体身份在定义核受体构象的能量景观方面起着关键作用。
