Departement de Biologie et de Génomique Structurales, Centre National de la Recherche Scientifique, Institut National de la Santé de la Recherche Médicale, Université de Strasbourg, 1 Rue Laurent Fries, 67404 Illkirch, France.
J Med Chem. 2010 Feb 11;53(3):1159-71. doi: 10.1021/jm9014636.
The vitamin D nuclear receptor is a ligand-dependent transcription factor that controls multiple biological responses such as cell proliferation, immune responses, and bone mineralization. Numerous 1 alpha,25(OH)(2)D(3) analogues, which exhibit low calcemic side effects and/or antitumoral properties, have been synthesized. We recently showed that the synthetic analogue (20S,23S)-epoxymethano-1 alpha,25-dihydroxyvitamin D(3) (2a) acts as a 1 alpha,25(OH)(2)D(3) superagonist and exhibits both antiproliferative and prodifferentiating properties in vitro. Using this information and on the basis of the crystal structures of human VDR ligand binding domain (hVDR LBD) bound to 1 alpha,25(OH)(2)D(3), 2 alpha-methyl-1 alpha,25(OH)(2)D(3), or 2a, we designed a novel analogue, 2 alpha-methyl-(20S,23S)-epoxymethano-1 alpha,25-dihydroxyvitamin D(3) (4a), in order to increase its transactivation potency. Here, we solved the crystal structures of the hVDR LBD in complex with the 4a (C23S) and its epimer 4b (C23R) and determined their correlation with specific biological outcomes.
维生素 D 核受体是一种配体依赖性转录因子，可控制多种生物学反应，如细胞增殖、免疫反应和骨矿化。已经合成了许多具有低钙副作用和/或抗肿瘤特性的 1α,25(OH)2D3 类似物。我们最近表明，合成类似物 (20S,23S)-环氧甲酰基-1α,25-二羟维生素 D3(2a) 作为 1α,25(OH)2D3 的超激动剂，在体外具有抗增殖和诱导分化特性。利用这些信息，并基于人 VDR 配体结合域 (hVDR LBD) 与 1α,25(OH)2D3、2α-甲基-1α,25(OH)2D3 或 2a 结合的晶体结构，我们设计了一种新型类似物 2α-甲基-(20S,23S)-环氧甲酰基-1α,25-二羟维生素 D3(4a)，以提高其转录激活能力。在这里，我们解决了 hVDR LBD 与 4a(C23S)及其差向异构体 4b(C23R)复合物的晶体结构，并确定了它们与特定生物学结果的相关性。
