Institute of Pharmaceutical Chemistry, Goethe University Frankfurt, Max-von-Laue-Str. 9, 60438 Frankfurt, Germany.
Structural Genomics Consortium, BMLS, Goethe-University Frankfurt, Max-von-Laue-Str. 15, 60438 Frankfurt, Germany.
Int J Mol Sci. 2020 Nov 11;21(22):8457. doi: 10.3390/ijms21228457.
The retinoid X receptor (RXR) is a ligand-sensing transcription factor acting mainly as a universal heterodimer partner for other nuclear receptors. Despite presenting as a potential therapeutic target for cancer and neurodegeneration, adverse effects typically observed for RXR agonists, likely due to the lack of isoform selectivity, limit chemotherapeutic application of currently available RXR ligands. The three human RXR isoforms exhibit different expression patterns; however, they share high sequence similarity, presenting a major obstacle toward the development of subtype-selective ligands. Here, we report the discovery of the saturated fatty acid, palmitic acid, as an RXR ligand and disclose a uniform set of crystal structures of all three RXR isoforms in an active conformation induced by palmitic acid. A structural comparison revealed subtle differences among the RXR subtypes. We also observed an ability of palmitic acid as well as myristic acid and stearic acid to induce recruitment of steroid receptor co-activator 1 to the RXR ligand-binding domain with low micromolar potencies. With the high, millimolar endogenous concentrations of these highly abundant lipids, our results suggest their potential involvement in RXR signaling.
视黄醇 X 受体 (RXR) 是一种配体感应转录因子，主要作为其他核受体的通用异二聚体伴侣发挥作用。尽管 RXR 激动剂被认为是癌症和神经退行性疾病的潜在治疗靶点，但通常观察到的不良反应可能是由于缺乏同工型选择性，限制了现有 RXR 配体的化学治疗应用。三种人类 RXR 同工型表现出不同的表达模式；然而，它们具有高度的序列相似性，这是开发亚型选择性配体的主要障碍。在这里，我们报告了饱和脂肪酸棕榈酸作为 RXR 配体的发现，并披露了所有三种 RXR 同工型在棕榈酸诱导的活性构象下的一组统一的晶体结构。结构比较揭示了 RXR 亚型之间的细微差异。我们还观察到棕榈酸以及肉豆蔻酸和硬脂酸具有以低微摩尔效力诱导甾体受体共激活因子 1 募集到 RXR 配体结合域的能力。由于这些高度丰富的脂质具有高、毫摩尔的内源性浓度，我们的结果表明它们可能参与了 RXR 信号转导。
