Faculty of Health Sciences/School of Pharmacy, University of Eastern Finland, P.O. Box 1627, Kuopio 70211, Finland.
J Mol Recognit. 2011 Sep-Oct;24(5):875-82. doi: 10.1002/jmr.1132.
The constitutive androstane receptor (CAR) possesses, unlike most other nuclear receptors, a pronounced basal activity in vitro whose structural basis is still not fully understood. Using comparative molecular dynamics simulations of CAR X-ray crystal structures, we evaluated the molecular basis for constitutive activity and ligand-dependent receptor activation. Our results suggest that a combination of van der Waals interactions and hydrogen bonds is required to maintain the activation helix in the active conformation also in absence of a ligand. Furthermore, we identified conformational rearrangements within the ligand-binding pocket upon agonist binding and an influence of CAR inducers pregnanedione and CITCO on the helical conformation of the activation helix. Based on the results a model for ligand-dependent CAR activation is suggested.
组成型雄烷受体（CAR）与大多数其他核受体不同，具有明显的体外基础活性，但其结构基础仍不完全清楚。我们使用 CAR X 射线晶体结构的比较分子动力学模拟，评估了组成型活性和配体依赖性受体激活的分子基础。我们的研究结果表明，在没有配体的情况下，范德华相互作用和氢键的组合对于维持激活螺旋处于活性构象是必需的。此外，我们在激动剂结合时鉴定了配体结合口袋内的构象重排，以及 pregnanedione 和 CITCO 等 CAR 诱导物对激活螺旋螺旋构象的影响。基于这些结果，提出了一个配体依赖性 CAR 激活的模型。
