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

Abstract

Until 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.

Neuropharmacology: a potential treatment strategy for dopamine-related brain disorders

Compounds that activate a gene-regulating protein called Nurr1 could help treat Parkinson’s disease and other brain disorders related to abnormal dopamine signaling. A team led by Kwang-Soo Kim from Harvard Medical School, Belmont, USA, reviews the various compounds, both synthetic and natural, known to enhance the activity of Nurr1. This protein binds DNA to regulate the expression of target genes and was long thought not to have such triggering molecules or ligands, which have recently been identified by the team. These activating compounds seem to protect dopamine-producing neurons from cell injury in various Parkinson’s-related cell and animal models. Given Nurr1’s role in the development, differentiation, and survival of dopaminergic neurons in the midbrain, these compounds could help boost the capacity of malfunctioning dopaminergic neurons in patients with Parkinson’s disease, schizophrenia, bipolar disorder, and other neuropsychiatric conditions.