Schwinn Marie K, DeLuca Hector F
Department of Biochemistry, University of Wisconsin-Madison, Madison, WI 53706, USA.
Arch Biochem Biophys. 2007 Sep 15;465(2):443-51. doi: 10.1016/j.abb.2007.06.015. Epub 2007 Jun 27.
To clarify the molecular mechanism for analog potency and selectivity, we investigated the ability of 1,25(OH)(2)D(3) analogs to recruit coactivators to the vitamin D receptor (VDR) transcriptional complex. Using a modified version of the avidin-biotin complex DNA binding assay, we discovered that 20S-analogs enhance the binding of specific coactivators to the transcriptional complex relative to natural hormone and that the enhanced binding occurs independently of vitamin D response element and cell type. With the exception of two of these coactivators, DRIP205 and DRIP240, all proteins were recruited to the transcriptional complex in a dose-dependent manner. While the results do not provide an explanation for tissue selectivity of 2-methylene-19-nor-(20S)-1,25-dihydroxyvitamin D(3) (2MD), they provide evidence that in the presence of a full-length side chain, the 20S configuration improves binding of specific proteins to the VDR transcriptional complex while modifications at carbon 2 do not.
为阐明类似物效力和选择性的分子机制，我们研究了1,25(OH)₂D₃类似物招募共激活因子至维生素D受体（VDR）转录复合物的能力。通过使用改良的抗生物素蛋白-生物素复合物DNA结合测定法，我们发现相对于天然激素，20S-类似物增强了特定共激活因子与转录复合物的结合，且这种增强的结合独立于维生素D反应元件和细胞类型发生。除了其中两个共激活因子DRIP205和DRIP240外，所有蛋白质均以剂量依赖性方式被招募至转录复合物。虽然这些结果并未对2-亚甲基-19-去甲-(20S)-1,25-二羟基维生素D₃（2MD）的组织选择性作出解释，但它们提供了证据，即在存在全长侧链的情况下，20S构型改善了特定蛋白质与VDR转录复合物的结合，而碳2位的修饰则不然。
