Assignment of the orphan nuclear receptor Nurr1 by NMR

Michiels, Paul; Atkins, Karen; Ludwig, Christian; Whittaker, Sara B.-M.; Dongen, Maria van; Günther, Ulrich L.

doi:10.1007/s12104-010-9210-4

Cited by 13 publications

(16 citation statements)

References 17 publications

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“…The LBD region of Nur77 is distinct from the typical LBD region present in other NRs. The human Nur77 crystal structure (Protein Data Bank-ID: 2QW4; ) shows that the Nur77 LBD region is blocked by hydrophobic residues ( 24 , 25 ). Several NRs have been reported to have a hydrophobic-cleft regulated by helices 3, 5 and 12, which is important for the recruitment of co-activators or co-repressors involved in transcriptional regulation ( 26 ).…”

Section: Structure Expression and Localization Of Nur77mentioning

confidence: 99%

Characteristics of Nur77 and its ligands as potential anticancer compounds (Review)

Chen

2018

Mol Med Report

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Nuclear receptor subfamily 4 group A member 1 (NR4A1; also termed Nur77/TR3/NGFIB), a member of the nuclear receptor superfamily, is expressed as an early response gene to regulate the expression of multiple target genes. Nur77 has the typical structure of a nuclear receptor, including an N-terminal domain, a DNA binding domain, and a ligand-binding domain. The expression and localization of Nur77 are closely associated with its roles in cell proliferation and apoptosis. Nur77 was first identified as an orphan receptor, the endogenous ligand of which has not yet been identified; however, an increasing number of compounds targeting Nur77 have been reported to have beneficial effects in the treatment of cancer and other diseases. This review provides a brief overview of the identification, structure, expression and localization, transcriptional role and non-genomic function of Nur77, and summarizes the ligands that have been shown to interact with Nur77, including cytosporone B, cisplatin, TMPA, PDNPA, CCE9, THPN, Z-ligustilide, celastrol and bisindole methane compounds, which may potentially be used to treat cancer in humans.

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Section: Structure Expression and Localization Of Nur77mentioning

confidence: 99%

Characteristics of Nur77 and its ligands as potential anticancer compounds (Review)

Chen

2018

Mol Med Report

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“…Nurr1 (NRA42) has been considered to function as a true orphan nuclear receptor on the basis of its LBP being filled with aromatic residues in the crystal structure of its LBD [139]. However, weakly binding Nurr1 ligands (K d = 20 μM) have been detected by 19 F NMR-based library screening [140] and missing NMR signals in two regions of the putative LBP also support a flexible pocket capable of interaction with a ligand [141]. …”

Section: Therapeutic Potentialmentioning

confidence: 99%

The retinoid X receptors and their ligands

Dawson

Xia

2012

Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biolog

331

325

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This chapter presents an overview of the current status of studies on the structural and molecular biology of the retinoid X receptor subtypes α, β, and γ (RXRs, NR2B1–3), their nuclear and cytoplasmic functions, post-transcriptional processing, and recently reported ligands. Points of interest are the different changes in the ligand-binding pocket induced by variously shaped agonists, the communication of the ligand–bound pocket with the coactivator binding surface and the heterodimerization interface, and recently identified ligands that are natural products, those that function as environmental toxins or drugs that had been originally designed to interact with other targets, as well as those that were deliberately designed as RXR-selective transcriptional agonists, synergists, or antagonists. Of these synthetic ligands, the general trend in design appears to be away from fully aromatic rigid structures to those containing partial elements of the flexible tetraene side chain of 9-cis-retinoic acid.

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“…A preliminary NMR study of the Nurr1 LBD indicated that residues comprising the putative LBP had shorter T 2 relaxation times, suggesting flexibility or dynamics on the μs-ms timescale (Michiels et al, 2010). We were therefore interested in the structural mechanism that could potentially allow Nurr1 to accommodate a bound natural ligand given the apparent collapsed Nurr1 LBP conformation captured by crystallography.…”

Section: Introductionmentioning

confidence: 99%

Defining a Canonical Ligand-Binding Pocket in the Orphan Nuclear Receptor Nurr1

et al. 2019

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Summary Nuclear receptor related 1 protein (Nurr1/NR4A2) is an orphan nuclear receptor (NR) that is considered to function without a canonical ligand-binding pocket (LBP). A crystal structure of the Nurrl ligand-binding domain (LBD) revealed no physical space in the conserved region where other NRs with solvent accessible apo-protein LBPs bind synthetic and natural ligands. Using solution NMR spectroscopy, hydrogen/deuterium exchange mass spectrometry, and molecular dynamics simulations, we show that the putative canonical Nurrl LBP is dynamic with high solvent accessibility, exchanges between two or more conformations on the microsecond-to-millisecond timescale, and can expand from the collapsed crystallized conformation to allow binding of unsaturated fatty acids. These findings should stimulate future studies to probe the ligandability and druggability of Nurrl for both endogenous and synthetic ligands, which could lead to new therapeutics for Nurrl-related diseases, including Parkinson’s disease and schizophrenia.

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Assignment of the orphan nuclear receptor Nurr1 by NMR

Cited by 13 publications

References 17 publications

Characteristics of Nur77 and its ligands as potential anticancer compounds (Review)

Characteristics of Nur77 and its ligands as potential anticancer compounds (Review)

The retinoid X receptors and their ligands

Defining a Canonical Ligand-Binding Pocket in the Orphan Nuclear Receptor Nurr1

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