Next-generation retinoid X receptor agonists increase ATRA signaling in organotypic epithelium cultures and have distinct effects on receptor dynamics.
Next-generation retinoid X receptor agonists increase ATRA signaling in organotypic epithelium cultures and have distinct effects on receptor dynamics.
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DOI：
10.1016/j.jbc.2022.102746
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发表时间：
2023-01
影响因子：
4.8
通讯作者：
Renfrow, Matthew B.
中科院分区：
文献类型：
--
作者：
Melo, Nathalia;Belyaeva, Olga V.;Berger, Wilhelm K.;Halasz, Laszlo;Yu, Jianshi;Pilli, Nagesh;Yang, Zhengrong;Klyuyeva, Alla V.;Elmets, Craig A.;Atigadda, Venkatram;Muccio, Donald D.;Kane, Maureen A.;Nagy, Laszlo;Kedishvili, Natalia Y.;Renfrow, Matthew B.
维甲酸X受体(RXRs)是一种核转录因子，与其他核受体配对，调节多种生理过程。尽管RXR是一个有效的治疗靶点，但目前只发现了几个RXR特异性配体(Rexinoid)，部分原因是Rexinoid如何选择性地调节RXR反应尚不清楚。此前，我们发现rexinid UAB30通过刺激全反式维甲酸(ATRA)的生物合成来增强人角质形成细胞中的全反式维甲酸(ATRA)信号。在这里，我们研究了新一代Rexinoid UAB110和UAB111的作用机制，它们在体外比UAB30和FDA批准的Targretin更有效。在比UAB30低50倍的浓度下，UAB110和UAB111都能增强人器官型上皮细胞中的ATRA信号。这与UAB110/111处理的器官型表皮ATRA比UAB30处理的ATRA增加2到5倍是一致的。此外，在0.2hμM时，UAB110/111ATRA基因的表达比塔格列汀强16倍。毒性较小、效力较强的UAB110也比Targretin引起更多差异基因表达的变化。此外，我们的氢氚交换质谱分析表明，这两种配体都降低了配体结合口袋的动力学，但也诱导了独特的动态反应，表明相对于UAB30，尤其是Helix 3，UAB110结合的亲和力更高。UAB110结合也显示通过Helix 8和Helix 9区域向二聚体界面的动力学增加。这些数据表明，UAB110和UAB111是RXR-RAR信号通路的有效激活剂，但它们通过不同的分子反应来完成对配体结合的激活。
Retinoid X receptors (RXRs) are nuclear transcription factors that partner with other nuclear receptors to regulate numerous physiological processes. Although RXR represents a valid therapeutic target, only a few RXR-specific ligands (rexinoids) have been identified, in part due to the lack of clarity on how rexinoids selectively modulate RXR response. Previously, we showed that rexinoid UAB30 potentiates all-trans-retinoic acid (ATRA) signaling in human keratinocytes, in part by stimulating ATRA biosynthesis. Here, we examined the mechanism of action of next-generation rexinoids UAB110 and UAB111 that are more potent in vitro than UAB30 and the FDA-approved Targretin. Both UAB110 and UAB111 enhanced ATRA signaling in human organotypic epithelium at a 50-fold lower concentration than UAB30. This was consistent with the 2- to 5- fold greater increase in ATRA in organotypic epidermis treated with UAB110/111 versus UAB30. Furthermore, at 0.2 μM, UAB110/111 increased the expression of ATRA genes up to 16-fold stronger than Targretin. The less toxic and more potent UAB110 also induced more changes in differential gene expression than Targretin. Additionally, our hydrogen deuterium exchange mass spectrometry analysis showed that both ligands reduced the dynamics of the ligand-binding pocket but also induced unique dynamic responses that were indicative of higher affinity binding relative to UAB30, especially for Helix 3. UAB110 binding also showed increased dynamics towards the dimer interface through the Helix 8 and Helix 9 regions. These data suggest that UAB110 and UAB111 are potent activators of RXR–RAR signaling pathways but accomplish activation through different molecular responses to ligand binding.
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影响因子：
4.1
作者：
Kane, MA;Chen, N;Napoli, JL
通讯作者：
Napoli, JL
影响因子：
64.5
作者：
HEYMAN, RA;MANGELSDORF, DJ;THALLER, C
通讯作者：
THALLER, C
氢/氘交换MS对蛋白质构象和动力学的分析。
影响因子：
7.4
作者：
Engen, John R.
通讯作者：
Engen, John R.
影响因子：
64.5
作者：
Bookout, Angie L.;Jeong, Yangsik;Mangelsdorf, David J.
通讯作者：
Mangelsdorf, David J.
影响因子：
45.3
作者：
Duvic, M;Hymes, K;Yocum, RC
通讯作者：
Yocum, RC