Hourai Shinji, Rodrigues Luis Cezar, Antony Pierre, Reina-San-Martin Bernardo, Ciesielski Fabrice, Magnier Benjamin Claude, Schoonjans Kristina, Mouriño Antonio, Rochel Natacha, Moras Dino
Institut de Génétique et de Biologie Moléculaire et Cellulaire, Département de Biologie et de Génomique Structurales, Université Louis Pasteur, Strasbourg F-67000, France.
Chem Biol. 2008 Apr;15(4):383-92. doi: 10.1016/j.chembiol.2008.03.016.
Vitamin D nuclear receptor (VDR), a ligand-dependent transcriptional regulator, is an important target for multiple clinical applications, such as osteoporosis and cancer. Since exacerbated increase of calcium serum level is currently associated with VDR ligands action, superagonists with low calcium serum levels have been developed. Based on the crystal structures of human VDR (hVDR) bound to 1alpha,25-dihydroxyvitamin D(3) and superagonists-notably, KH1060-we designed a superagonist ligand. In order to optimize the aliphatic side chain conformation with a subsequent entropy benefit, we incorporated an oxolane ring and generated two stereo diasteromers, AMCR277A and AMCR277B. Only AMCR277A exhibits superagonist activity in vitro, but is as calcemic in vivo as the natural ligand. The crystal structures of the complexes between the ligand binding domain of hVDR and these ligands provide a rational approach to the design of more potent superagonist ligands for potential clinical application.
维生素D核受体（VDR）是一种依赖配体的转录调节因子，是多种临床应用（如骨质疏松症和癌症）的重要靶点。由于目前血清钙水平的加剧升高与VDR配体的作用相关，因此已开发出具有低血清钙水平的超级激动剂。基于与1α,25-二羟基维生素D3和超级激动剂（特别是KH1060）结合的人VDR（hVDR）的晶体结构，我们设计了一种超级激动剂配体。为了通过随后的熵增益优化脂肪族侧链构象，我们引入了一个氧杂环戊烷环并生成了两种立体非对映异构体，AMCR277A和AMCR277B。只有AMCR277A在体外表现出超级激动剂活性，但在体内的血钙作用与天然配体相同。hVDR配体结合域与这些配体之间复合物的晶体结构为设计更有效的超级激动剂配体以用于潜在临床应用提供了一种合理的方法。
