Germain Pierre, Kammerer Sabrina, Pérez Efrén, Peluso-Iltis Carole, Tortolani David, Zusi F Christopher, Starrett John, Lapointe Philippe, Daris Jean-Paul, Marinier Anne, de Lera Angel R, Rochel Natacha, Gronemeyer Hinrich
Institut de Génétique et de Biologie Moléculaire et Cellulaire CNRS/INSERM/ULP, BP 10142, 67404 Illkirch Cedex, CU de Strasbourg, France.
EMBO Rep. 2004 Sep;5(9):877-82. doi: 10.1038/sj.embor.7400235.
The crystal structure of the ligand-binding domain of RARbeta, a suspect tumour suppressor, reveals important features that distinguish it from the two other RAR isotypes. The most striking difference is an extra cavity allowing RARbeta to bind more bulky agonists. Accordingly, we identified a ligand that shows RARbeta selectivity with a 100-fold higher affinity to RARbeta than to alpha or gamma isotypes. The structural differences between the three RAR ligand-binding pockets revealed a rationale explaining how a single retinoid can be at the same time an RARalpha, gamma antagonist and an RARbeta agonist. In addition, we demonstrate how to generate an RARbeta antagonist by gradually modifying the bulkiness of a single substitution. Together, our results provide structural guidelines for the synthesis of RARbeta-selective agonists and antagonists, allowing for the first time to address pharmacologically the tumour suppressor role of RARbeta in vitro and in animal models.
视黄酸受体β（RARβ）的配体结合域是一种可疑的肿瘤抑制因子，其晶体结构揭示了一些重要特征，使其有别于其他两种RAR亚型。最显著的差异是存在一个额外的腔，使得RARβ能够结合更大的激动剂。因此，我们鉴定出一种配体，它对RARβ具有选择性，与RARα或γ亚型相比，对RARβ的亲和力高100倍。三种RAR配体结合口袋之间的结构差异揭示了一种原理，解释了单一类视黄醇如何能同时作为RARα、γ拮抗剂和RARβ激动剂。此外，我们展示了如何通过逐步改变单个取代基的体积来生成RARβ拮抗剂。总之，我们的结果为合成RARβ选择性激动剂和拮抗剂提供了结构指导原则，首次使得在体外和动物模型中从药理学角度研究RARβ的肿瘤抑制作用成为可能。
