Department of Pharmacology and Physiology, Saint Louis University School of Medicine, St. Louis, MO, 63104, USA.
Center for Clinical Pharmacology, Washington University School of Medicine, University of Health Sciences & Pharmacy, St. Louis, MO, 63110, USA.
Nat Commun. 2022 Nov 21;13(1):7131. doi: 10.1038/s41467-022-34892-4.
The nuclear receptor REV-ERB plays an important role in a range of physiological processes. REV-ERB behaves as a ligand-dependent transcriptional repressor and heme has been identified as a physiological agonist. Our current understanding of how ligands bind to and regulate transcriptional repression by REV-ERB is based on the structure of heme bound to REV-ERB. However, porphyrin (heme) analogues have been avoided as a source of synthetic agonists due to the wide range of heme binding proteins and potential pleotropic effects. How non-porphyrin synthetic agonists bind to and regulate REV-ERB has not yet been defined. Here, we characterize a high affinity synthetic REV-ERB agonist, STL1267, and describe its mechanism of binding to REV-ERB as well as the method by which it recruits transcriptional corepressor both of which are unique and distinct from that of heme-bound REV-ERB.
核受体 REV-ERB 在多种生理过程中发挥着重要作用。REV-ERB 作为一种配体依赖性转录阻遏物发挥作用，而血红素已被确定为一种生理激动剂。我们目前对配体如何与 REV-ERB 结合以及调节转录阻遏的理解是基于血红素与 REV-ERB 结合的结构。然而，由于血红素结合蛋白的广泛存在和潜在的多效性影响，卟啉（血红素）类似物一直被避免作为合成激动剂的来源。非卟啉合成激动剂如何与 REV-ERB 结合并调节其活性尚未得到明确界定。在这里，我们描述了一种高亲和力的合成 REV-ERB 激动剂 STL1267，并描述了它与 REV-ERB 结合的机制以及它招募转录共阻遏物的方法，这些都与血红素结合的 REV-ERB 独特且不同。
