Identification of Small Molecule Agonists of the Orphan Nuclear Receptors Liver Receptor Homolog-1 and Steroidogenic Factor-1

Whitby, Richard J.; Dixon, Sally; Maloney, Patrick; Delerive, Philippe; Goodwin, Bryan; Parks, Derek J.; Willson, Timothy M.

doi:10.1021/jm060990k

Cited by 86 publications

(88 citation statements)

References 24 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…1A and Table S1). In comparison, affinity of RJW100 (20), a derivative of the synthetic NR5A ligand GSK8470 (21), was notably worse than PI(3,4,5)P 3 with an apparent K d of 1,200 ± 270 nM, as determined here by electrophoretic mobility-shift in native gels. We also noted that DLPC, a short-chained exogenous phosphatidylcholine LRH-1 ligand (16,22), binds SF-1 poorly.…”

Section: Significancementioning

confidence: 59%

The signaling phospholipid PIP ₃ creates a new interaction surface on the nuclear receptor SF-1

Blind¹,

Sablin

Kuchenbecker

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

129

View full text Add to dashboard Cite

The signaling phosphatidylinositol lipids PI(4,5)P 2 (PIP 2 ) and PI (3,4,5)P 3 (PIP 3 ) bind nuclear receptor 5A family (NR5As), but their regulatory mechanisms remain unknown. Here, the crystal structures of human NR5A1 (steroidogenic factor-1, SF-1) ligand binding domain (LBD) bound to PIP 2 and PIP 3 show the lipid hydrophobic tails sequestered in the hormone pocket, as predicted. However, unlike classic nuclear receptor hormones, the phosphoinositide head groups are fully solvent-exposed and complete the LBD fold by organizing the receptor architecture at the hormone pocket entrance. The highest affinity phosphoinositide ligand PIP 3 stabilizes the coactivator binding groove and increases coactivator peptide recruitment. This receptor-ligand topology defines a previously unidentified regulatory protein-lipid surface on SF-1 with the phosphoinositide head group at its nexus and poised to interact with other proteins. This surface on SF-1 coincides with the predicted binding site of the corepressor DAX-1 (dosage-sensitive sex reversal, adrenal hypoplasia critical region on chromosome X), and importantly harbors missense mutations associated with human endocrine disorders. Our data provide the structural basis for this poorly understood cluster of human SF-1 mutations and demonstrates how signaling phosphoinositides function as regulatory ligands for NR5As.T he existence of nuclear, nonmembrane pools of signaling phosphorylated derivatives of phosphatidylinositols or phosphoinositides (PIP n ) was reported over two decades ago (1-3). Consistent with these early reports, lipid-modifying enzymes responsible for phosphoinositide metabolism were also found in the nucleus (4-7); however, the function of PIP n in this cellular compartment remains poorly defined. The nuclear receptors (NRs) steroidogenic factor 1 (SF-1, NR5A1) and liver receptor homolog 1 (LRH-1, NR5A2) bind phosphoinositides as well as other phospholipids in their large hydrophobic pockets (8-13). The ability of NR5As to interact with PIP n is well-conserved with the Caenorhabditis elegans ortholog nhr-25 able to bind both PIP 2 and PIP 3 (14). That phosphoinositides might serve as endogenous NR5A ligands is suggested by the fact that elevating cellular pools of PIP 3 increases SF-1 activity (15) and that impairing PIP 3 uptake decreases SF-1 activity (12). Further, when purified from mammalian cells, the phosphoinositide PIP 2 is found associated with SF-1 and can be modified by the lipid kinase, IPMK, as well as the lipid phosphatase, PTEN (13). Taken together, these data suggest that signaling phosphoinositides are biologically relevant ligands for SF-1.Phosphoinositide ligands diverge chemically from classic NR hormones in that they contain a long, extended hydrophobic moiety and a prominent hydrophilic head group, which is inherently incompatible with the hydrophobic core of the NR5A ligand-binding pocket. Our previous structural analyses of SF-1 bound to phosphatidylcholine suggest that the acyl tails of phosphoinositides should be sequestered...

show abstract

Section: Significancementioning

confidence: 59%

The signaling phospholipid PIP ₃ creates a new interaction surface on the nuclear receptor SF-1

Blind¹,

Sablin

Kuchenbecker

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

129

View full text Add to dashboard Cite

show abstract

“…The search for ligands/agonists for SHP using fluorescence resonance energy transfer (FRET)-based biochemical detection tools suggests that GSK8470 is an inducer of SHP expression [43] and AHPN/3-Cl-AHPC and their analogues bind specifically to SHP, and these synthetic molecules may turnout to be a possible ligand for SHP, pending more confirmatory results [44,45].…”

Section: Inducers Of Shp Promoter and Gene Expressionmentioning

confidence: 99%

Molecular Basis of Endocrine Regulation by Orphan Nuclear Receptor Small Heterodimer Partner

2008

View full text Add to dashboard Cite

Abstract. Nuclear receptors (NRs) are a unique superfamily of transcription factors (TFs) which are involved in and play a crucial role in almost all aspects of mammalian physiology. Small Heterodimer Partner (SHP; NR0B2), an exceptional member of this superfamily of NRs, have been identified as a key regulatory factor of the transcription of a variety of genes involved in diverse metabolic pathways, and are thereby an important factor in a variety of physiological functions. Since its discovery a decade ago, considerable progress has been made in the elucidation of the underlying mechanism by which SHP regulates various metabolic processes, and the results of previous studies support its importance in the maintenance of metabolic homeostasis. In this review, we have evaluated the current state of understanding of the molecular mechanisms and the resultant physiological interpretations governed by SHP. SMALL Heterodimer Partner is a unique member of the mammalian nuclear receptor superfamily, which is clearly distinct from the conventional nuclear receptors, both structurally and functionally. It is classified into the "orphan" subfamily, due to the absence of any known ligand for this receptor, and appears to function as a transcriptional co-regulator of numerous nuclear receptors and transcription factors. The dosage-sensitive sex reversal-adrenal hypoplasia congenital region gene on the X chromosome, gene-1 (DAX-1; NR0B1) is the closest relative to SHP. Both belong to the same subfamily, and both share considerable functional and structural similarities with SHP. SHP owes its place in the nuclear receptor family to the presence of a putative ligand binding domain (LBD), although it lacks the classical DNA binding domain (DBD) which is generally detected among other nuclear receptors. Intensive research conducted following its discovery last decade has resulted in a clearer understanding of the molecular basis for the inhibitory functions of SHP on a variety of metabolic processes, thereby providing us with ample evidence regarding its importance as a key regulator in a number of signaling pathways [1,2]. Hub-based topological analysis of the nuclear receptor network has demonstrated the extensive connections existing among these receptors as the result of their similarity in terms of interaction and tissue expression, as well as a considerable number of feedback loops that work in concert in this network, with SHP playing a principal role as the hub protein within this network [3]. In this review, we have attempted to survey the entirety of the information available thus far concerning the structural and functional aspects of the orphan nuclear receptor SHP, hoping to acquire a detailed understanding of the physiological significance of the activity of SHP.

show abstract

“…Small-molecule dual agonists of LRH-1 and SF-1 were recently identified and shown to affect the expression of SHP, a target gene of LRH-1, in hepatocytes (Whitby et al, 2006). Other groups have reported findings that further strengthen this hypothesis, in particular with the identification of synthetic ligands for the Nurr family orphan nuclear receptors (Dubois et al, 2006;Hintermann et al, 2007).…”

Section: Discussionmentioning

confidence: 94%

“…Interestingly enough, the SF-1/LRH-1 dual agonist recently identified by Whitby et al (2006) also contains an alkyl chain. Although not structurally interested to either AC-45594 or sphingosine, it is intriguing that chemistries modulating SF-1 activity identified so far share this alkyl moiety.…”

Section: Discussionmentioning

confidence: 99%

Identification of the First Synthetic Steroidogenic Factor 1 Inverse Agonists: Pharmacological Modulation of Steroidogenic Enzymes

Tredici¹,

Andersen²,

Currier³

et al. 2007

Mol Pharmacol

View full text Add to dashboard Cite

Steroidogenic factor SF-1, a constitutively active nuclear hormone receptor, is essential to the development of adrenal and gonadal glands and acts as a shaping factor of sexual determination and differentiation. Its effects are exerted primarily through the control of the synthesis of steroid hormones. The functional cell-based assay Receptor Selection and Amplification Technology (R-SAT) was used to identify potent and selective SF-1 inverse agonists through the screening of a chemical library of drug-like small-molecule entities. Among them, 4-(heptyloxy)phenol (AC-45594), a prototype inverse agonist lead, was used to show that SF-1 constitutive activity can be pharmacologically modulated by a synthetic ligand. In a physiological system of endocrine function, the expression of several reported SF-1 target genes, including SF-1 itself, was inhibited by treatment with AC-45594 and analogs. Thus, pharmacological modulation of SF-1 is critical to its function as an endocrine master regulator and has potentially important consequences to diseases in which SF-1 activity is critical.

show abstract

Identification of Small Molecule Agonists of the Orphan Nuclear Receptors Liver Receptor Homolog-1 and Steroidogenic Factor-1

Cited by 86 publications

References 24 publications

The signaling phospholipid PIP ₃ creates a new interaction surface on the nuclear receptor SF-1

The signaling phospholipid PIP ₃ creates a new interaction surface on the nuclear receptor SF-1

Molecular Basis of Endocrine Regulation by Orphan Nuclear Receptor Small Heterodimer Partner

Identification of the First Synthetic Steroidogenic Factor 1 Inverse Agonists: Pharmacological Modulation of Steroidogenic Enzymes

Contact Info

Product

Resources

About

Identification of Small Molecule Agonists of the Orphan Nuclear Receptors Liver Receptor Homolog-1 and Steroidogenic Factor-1

Cited by 86 publications

References 24 publications

The signaling phospholipid PIP 3 creates a new interaction surface on the nuclear receptor SF-1

The signaling phospholipid PIP 3 creates a new interaction surface on the nuclear receptor SF-1

Molecular Basis of Endocrine Regulation by Orphan Nuclear Receptor Small Heterodimer Partner

Identification of the First Synthetic Steroidogenic Factor 1 Inverse Agonists: Pharmacological Modulation of Steroidogenic Enzymes

Contact Info

Product

Resources

About

The signaling phospholipid PIP ₃ creates a new interaction surface on the nuclear receptor SF-1

The signaling phospholipid PIP ₃ creates a new interaction surface on the nuclear receptor SF-1