Graduate School of Biomedical Science, ‡Institute of Biomaterials and Bioengineering, and §Medical Research Institute, Tokyo Medical and Dental University , Bunkyo-ku, Tokyo 113-8510, Japan.
J Med Chem. 2013 Sep 12;56(17):6745-60. doi: 10.1021/jm400537h. Epub 2013 Aug 29.
The vitamin D receptor (VDR), a member of the nuclear receptor superfamily, functions as a ligand-dependent transcription factor for various genes. Hereditary vitamin D-resistant rickets (HVDRR), an autosomal recessive disease, is caused by mutations in the VDR. In particular, the missense mutations R274L and W286R in the ligand-binding domain of the VDR can severely reduce or even eliminate natural hormone responsiveness. Here, we report a crystal structure analysis of the R270L and W282R mutants of rat VDR (human R274L and W286R, respectively) in complex with the natural hormone and synthetic ligands. We also studied the folding properties of the mutant proteins by using circular dichroism spectra. Our study indicates that these mutations result in only local structural modifications. We discuss why these mutations disrupt the VDR function and provide clues to develop effective ligands for the treatment of HVDRR.
维生素 D 受体 (VDR) 是核受体超家族的成员，作为配体依赖性转录因子，调节多种基因的表达。遗传性维生素 D 抵抗性佝偻病 (HVDRR) 是一种常染色体隐性遗传疾病，由 VDR 基因突变引起。特别是 VDR 配体结合域中的错义突变 R274L 和 W286R 可严重降低甚至消除天然激素的反应性。在此，我们报告了大鼠 VDR 的 R270L 和 W282R 突变体（分别为人 VDR 的 R274L 和 W286R）与天然激素和合成配体复合物的晶体结构分析。我们还通过圆二色光谱研究了突变蛋白的折叠性质。我们的研究表明，这些突变仅导致局部结构修饰。我们讨论了这些突变如何破坏 VDR 功能，并为开发治疗 HVDRR 的有效配体提供了线索。
