Orphan nuclear receptor 4A1 (NR4A1) and novel ligands

2021 ◽  
Author(s):  
Stephen Safe ◽  
Rupesh Shrestha ◽  
Kumaravel Mohankumar
Keyword(s):  
Fatty Acids ◽  
Nuclear Receptor ◽  
Inflammatory Diseases ◽  
Orphan Nuclear Receptor ◽  
Orphan Receptors ◽  
Endogenous Ligands ◽  
Ligand Structure ◽  
Cell Tissue ◽  
Human Genes ◽  
Clinical Potential

Abstract The nuclear receptor (NR) superfamily of transcription factors encodes expression of 48 human genes that are important for maintaining cellular homeostasis and in pathophysiology, and this has been observed for all sub-families including orphan receptors for which endogenous ligands have not yet been identified. The orphan NR4A1 (Nur77 and TR3) and other members of this sub-family (NR4A2 and NR4A3) are immediate early genes induced by diverse stressors, and these receptors play an important role in the immune function and are up-regulated in some inflammatory diseases including solid tumors. Although endogenous ligands for NR4A have not been identified, several different classes of compounds have been characterized as NR4A1 ligands that bind the receptor. These compounds include cytosporone B and structurally related analogs, bis-indole derived (CDIM) compounds, the triterpenoid celastrol and a number of other chemicals including polyunsaturated fatty acids. NR4A1 ligands bind different regions/surfaces of NR4A1 and exhibit selective NR4A1 modulator (SNR4AM) activities that are dependent on ligand structure and cell/tissue context. NR4A1 ligands exhibit pharmacologic activities in studies on cancer, endometriosis metabolic and inflammatory diseases and are promising agents with clinical potential for treating multiple diseases.

scholarly journals Potent synthetic and endogenous ligands for the adopted orphan nuclear receptor Nurr1

2021 ◽  
Vol 53 (1) ◽  
pp. 19-29
Author(s):  
Yongwoo Jang ◽  
Woori Kim ◽  
Pierre Leblanc ◽  
Chun-Hyung Kim ◽  
Kwang-Soo Kim
Keyword(s):  
Ligand Binding ◽  
Nuclear Receptor ◽  
Inflammatory Diseases ◽  
Binding Pocket ◽  
Therapeutic Interventions ◽  
Orphan Nuclear Receptor ◽  
Endogenous Ligands ◽  
Structural Conformation ◽  
Narrow Space

AbstractUntil recently, Nurr1 (NR4A2) was known as an orphan nuclear receptor without a canonical ligand-binding domain, featuring instead a narrow and tight cavity for small molecular ligands to bind. In-depth characterization of its ligand-binding pocket revealed that it is highly dynamic, with its structural conformation changing more than twice on the microsecond-to-millisecond timescale. This observation suggests the possibility that certain ligands are able to squeeze into this narrow space, inducing a conformational change to create an accessible cavity. The cocrystallographic structure of Nurr1 bound to endogenous ligands such as prostaglandin E1/A1 and 5,6-dihydroxyindole contributed to clarifying the crucial roles of Nurr1 and opening new avenues for therapeutic interventions for neurodegenerative and/or inflammatory diseases related to Nurr1. This review introduces novel endogenous and synthetic Nurr1 agonists and discusses their potential effects in Nurr1-related diseases.

scholarly journals Identification of a Binding Site for Unsaturated Fatty Acids in the Orphan Nuclear Receptor Nurr1

2016 ◽  
Vol 11 (7) ◽  
pp. 1795-1799 ◽  
Author(s):  
Ian Mitchelle S. de Vera ◽  
Pankaj K. Giri ◽  
Paola Munoz-Tello ◽  
Richard Brust ◽  
Jakob Fuhrmann ◽  
...  
Keyword(s):  
Fatty Acids ◽  
Binding Site ◽  
Nuclear Receptor ◽  
Unsaturated Fatty Acids ◽  
Orphan Nuclear Receptor

scholarly journals 6-Mercaptopurine augments glucose transport activity in skeletal muscle cells in part via a mechanism dependent upon orphan nuclear receptor NR4A3

2013 ◽  
Vol 305 (9) ◽  
pp. E1081-E1092 ◽  
Author(s):  
Qinglan Liu ◽  
Xiaolin Zhu ◽  
Lusheng Xu ◽  
Yuchang Fu ◽  
W. Timothy Garvey
Keyword(s):  
Skeletal Muscle ◽  
Glucose Transport ◽  
Nuclear Receptor ◽  
Inflammatory Diseases ◽  
Muscle Cells ◽  
Skeletal Muscle Cells ◽  
Target Cells ◽  
Dependent Manner ◽  
Orphan Nuclear Receptor ◽  
Transport Activity

The purine anti-metabolite 6-mercaptopurine (6-MP) is widely used for the treatment of leukemia and inflammatory diseases. The cellular effects of 6-MP on metabolism remain unknown; however, 6-MP was recently found to activate the orphan nuclear receptor NR4A3 in skeletal muscle cell lines. We have reported previously that NR4A3 (also known as NOR-1, MINOR) is a positive regulator of insulin sensitivity in adipocytes. To further explore the role of NR4A3 activation in insulin action, we explored whether 6-MP activation of NR4A3 could modulate glucose transport system activity in L6 skeletal muscle cells. We found that 6-MP increased both NR4A3 expression and NR4A3 transcriptional activity and enhanced glucose transport activity via increasing GLUT4 translocation in both basal and insulin-stimulated L6 cells in an NR4A3-dependent manner. Furthermore, 6-MP increased levels of phospho-AS160, although this effect was not modulated by NR4A3 overexpression or knockdown. These primary findings provide a novel proof of principle that 6-MP, a small molecule NR4A3 agonist, can augment glucose uptake in insulin target cells, although this occurs via both NR4A3-dependent and -independent actions; the latter is related to an increase in phospho-AS160. These results establish a novel target for development of new treatments for insulin resistance.

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