Differential Action on Coregulator Interaction Defines Inverse Retinoid Agonists and Neutral Antagonists
Differential Action on Coregulator Interaction Defines Inverse Retinoid Agonists and Neutral Antagonists
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DOI：
10.1016/j.chembiol.2009.03.008
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发表时间：
2009-05-29
影响因子：
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通讯作者：
Gronemeyer, Hinrich
中科院分区：
文献类型：
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作者：
Germain, Pierre;Gaudon, Claudine;Gronemeyer, Hinrich
视黄酸受体（RAR）是控制多种生理过程的配体依赖性转录因子。RAR通过调节控制细胞生长、分化、存活和死亡的基因网络发挥其功能。揭示合成配体指导核受体特异性和功能性的分子细节是合理药物开发的关键。在这里，我们定义了（E）-4-[2-[5，6-二氢-5，5-二甲基-8-甲基-1，2，3-三唑-1-基]-N-甲基-1，2，3-三唑-1-基]-N-甲基-1，2，3-三唑-1-酮的分子基础。（2-苯乙炔基）萘-2-基]乙烯-1-基]苯甲酸（BMS 204，493）作为反向泛RAR激动剂，并定义4-[5，6-二氢-5，5-二甲基-8-（三氟甲基）苯基]-N-甲基-N-甲基-N-（三氟甲基）苯基]-N-甲基-N-（三氟甲基）-N-甲基-N-（三氟甲基）苯基]-N-（三氟甲基）苯基。（喹啉-3-基）萘-2-甲酰胺基]苯甲酸（BMS 195，614）作为中性RAR α选择性拮抗剂。我们揭示了由配体施加在受体上的差异辅调节因子相互作用的细节，并表明H12的锚定在两个配体的存在下从根本上是不同的，从而解释了所观察到的对辅激活因子和辅阻遏因子相互作用的影响。这些配体将有助于研究RAR的组成性活性的作用，特别是肿瘤抑制因子RAR β，其相对于其他RAR的特异性功能仍然难以捉摸。
Retinoic acid receptors (RARs) are ligand-dependent transcription factors that control a plethora of physiological processes. RARs exert their functions by regulating gene networks controlling cell growth, differentiation, survival, and death. Uncovering the molecular details by which synthetic ligands direct specificity and functionality of nuclear receptors is key to rational drug development. Here we define the molecular basis for (E)-4-[2-[5,6-Dihydro-5,5-dimethyl-8-(2-phenylethynyl)naphthalen-2-yl]ethen-1-yl]benzoic acid (BMS204,493) acting as the inverse pan-RAR agonist and define 4-[5,6-Dihydro-5,5-dimethyl-8-(quinolin-3-yl)naphthalen-2-carboxamido] benzoic acid (BMS195,614) as the neutral RAR alpha-selective antagonist. We reveal the details of the differential coregulator interactions imposed on the receptor by the ligands and show that the anchoring of H12 is fundamentally distinct in the presence of the two ligands, thus accounting for the observed effects on coactivator and corepressor interactions. These ligands will facilitate studies on the role of the constitutive activity of RARs, particularly of the tumor suppressor RAR beta, whose specific functions relative to other RARs have remained elusive.