Huet Tiphaine, Maehr Hubert, Lee Hong Jin, Uskokovic Milan R, Suh Nanjoo, Moras Dino, Rochel Natacha
Département de Biologie et de Génomique Structurales, IGBMC (Institut de Génétique et de Biologie Moléculaire et Cellulaire), Centre National de la Recherche Scientifique, Institut National de la Santé de la Recherche Méedicale, Université de Strasbourg, 1 rue Laurent Fries, 67404 Illkirch, France.
Medchemcomm. 2011;2(5):424-429. doi: 10.1039/C1MD00059D.
Derivatives of vitamin D(3) containing a second side-chain emanating at C-20 are known as gemini and act as vitamin D receptor agonists. Recently, two of these, namely Gemini-0072 and the epimeric Gemini-0097, were selected for further studies in view of their high biological activities and lack of hypercalcemic effects. We now show that the two analogs recruit coactivator SRC-1 better than the parental gemini and act as VDR superagonists. The crystal structures of complexes of zVDR with Gemini-0072 and Gemini-0097 indicate that these ligands induce an extra cavity within the ligand-binding pocket similar to gemini and that their superagonistic activity is due to an increased stabilization of helix H12.
含有在C-20处发出的第二条侧链的维生素D(3)衍生物被称为双联体，并且作为维生素D受体激动剂发挥作用。最近，鉴于它们的高生物活性和缺乏高钙血症效应，其中两种，即Gemini-0072和差向异构的Gemini-0097，被选用于进一步研究。我们现在表明，这两种类似物比亲本双联体更好地募集共激活因子SRC-1，并作为VDR超激动剂发挥作用。zVDR与Gemini-0072和Gemini-0097的复合物的晶体结构表明，这些配体在配体结合口袋内诱导出一个类似于双联体的额外腔，并且它们的超激动活性归因于螺旋H12稳定性的增加。
