Structure and Dynamics of the Liver Receptor Homolog 1–PGC1<i>α</i> Complex

Mays, Suzanne G.; Okafor, C. Denise; Tuntland, Micheal L.; Whitby, Richard J.; Dharmarajan, Venkatasubramanian; Stec, Józef; Griffin, Patrick R.; Ortlund, Eric A.

doi:10.1124/mol.117.108514

Cited by 23 publications

(61 citation statements)

References 43 publications

(75 reference statements)

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“…As previously observed 13,15 , RJW100 stabilizes the LRH-1 ligand binding domain (LBD) by around 3 ºC relative to a PL ligand in DSF assays ( Figure 3A). While the R 2 -and R 3 -modified compounds (9-23) destabilize the receptor relative to RJW100 ( Figure 3A) and tend to be poor activators ( Figure 2C, S1), certain R 1 modifications are highly stabilizing, with Tm values 3-8 °C higher than RJW100 ( Figure 3A and online supplementary material).…”

Section: Introductionsupporting

confidence: 81%

Development of the first low nanomolar Liver Receptor Homolog-1 agonist through structure-guided design

Mays

Flynn

Corneilson

et al. 2019

Preprint

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As a key regulator of metabolism and inflammation, the orphan nuclear hormone receptor, Liver Receptor Homolog-1 (LRH-1), has potential as a therapeutic target for diabetes, nonalcoholic fatty liver disease, and inflammatory bowel diseases. Discovery of LRH-1 modulators has been difficult, in part due to the tendency for synthetic compounds to bind unpredictably within the lipophilic binding pocket. Using a structure-guided approach, we exploited a newly-discovered polar interaction to lock agonists in a consistent orientation. This enabled the discovery of the first low nanomolar LRH-1 agonist, one hundred times more potent than the best previous modulator. We elucidate a novel mechanism of action that relies upon specific polar interactions deep in the LRH-1 binding pocket. In an organoid model of inflammatory bowel disease, the new agonist increases expression of LRH-1-conrolled steroidogenic genes and promotes anti-inflammatory gene expression changes. These studies constitute major progress in developing LRH-1 modulators with potential clinical utility.de novo lipogenesis 6 . In addition, targeting LRH-1 in the gut has therapeutic potential for inflammatory bowel disease, where LRH-1 overexpression ameliorates disease-associated inflammation and cell death 10 .While small molecule LRH-1 modulators are highly sought, the large and lipophilic LRH-1 binding pocket has been extremely challenging to target. A promising class of agonists developed by Whitby and colleagues features a bicyclic hexahydropentalene core scaffold 11-12 . The beststudied of this class, named RJW100, was discovered as a part of an extensive synthetic effort to improve acid stability and efficacy of a related compound, GSK8470 12 ( Figure 1A). We recently determined the crystal structure of LRH-1 bound to RJW100 and made a surprising discovery: it exhibits a completely different binding mode than GSK8470, such that the bicyclic cores of the two agonists are perpendicular to each other ( Figure 1A) 13 . As a result, the two compounds use different mechanisms to activate LRH-1 but exhibit similar activation profiles in luciferase reporter assays 13 . A tendency for ligands in this class to bind unpredictably in the hydrophobic pocket has likely been a confounding factor in agonist design; however, insights from the LRH-1-RJW100 structure have provided new strategies to improve activity.In the LRH-1-RJW100 crystal structure, the ligand hydroxyl group contacts a network of water molecules deep in the ligand binding pocket ( Figure 1B). This water network coordinates a small group of polar residues (e.g. Thr352, His390, and Arg393) in an otherwise predominantly hydrophobic pocket. The endo RJW100 diastereomer adopts a nearly identical pose and makes the same water-mediated contact with Thr352, supporting the idea that this interaction is a primary driver of ligand orientation 13 . Using both a RJW100 analog lacking a hydroxyl group and a LRH-1 Thr352Val mutation, we demonstrated that this interaction is required for RJW100-mediated activation o...

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Section: Introductionsupporting

confidence: 81%

Development of the first low nanomolar Liver Receptor Homolog-1 agonist through structure-guided design

Mays

Flynn

Corneilson

et al. 2019

Preprint

Self Cite

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“…When regulating mitochondrial biogenesis, LRH‐1 activation induces an increase in mitochondrial DNA content that is associated with an increase in the expression of PGC‐1α. PGC‐1α is not only a well‐known inducer of mitochondrial biogenesis but also an LRH‐1 coactivator . This suggests the existence of a self‐supporting feed‐forward loop in which LRH‐1 activation reinforces its own transactivation through increased activity of its key coregulator.…”

Section: Discussionmentioning

confidence: 99%

“…PGC-1α is not only a wellknown inducer of mitochondrial biogenesis (38) but also an LRH-1 coactivator. (9) This suggests the existence of a self-supporting feed-forward loop in which LRH-1 activation reinforces its own transactivation through increased activity of its key coregulator. The identification of Pemt (39,40) for PC production, and potentially several genes for the generation of specific longer-chain unsaturated PC species (11) as LRH-1 target genes, suggests an additional loop in which LRH-1 induces expression of its own agonist(s).…”

Section: Discussionmentioning

confidence: 99%

“…Shp gene expression is also induced by the bile acid receptor farnesoid X receptor, resulting in a negative feedback loop in which elevated hepatic bile acid levels suppress bile acid production through inhibition of LRH‐1 transactivation . Particularly in the agonist bound state, LRH‐1 transactivation can be positively regulated by coactivators, with recent structural evidence indicating an important role for peroxisomal proliferator gamma coactivator‐1‐alpha (PGC‐1α; PPARGC1A) …”

mentioning

confidence: 99%

“…(8) Particularly in the agonist bound state, LRH-1 transactivation can be positively regulated by coactivators, with recent structural evidence indicating an important role for peroxisomal proliferator gamma coactivator-1-alpha (PGC-1α; PPARGC1A). (9) In addition to controlling bile acid homeostasis, several reports suggest that LRH-1 targets different metabolic pathways. We identified dilauroylphosphatidylcholine (DLPC), an unusual PC species with two saturated 12-carbon fatty acid acyl chains, as an exogenous LRH-1 agonist and showed that DLPC treatment could attenuate fatty liver and improve insulin sensitivity by repressing lipogenesis.…”

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confidence: 99%

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Methyl‐Sensing Nuclear Receptor Liver Receptor Homolog‐1 Regulates Mitochondrial Function in Mouse Hepatocytes

et al. 2019

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Background and Aims Liver receptor homolog‐1 (LRH‐1; NR5A2) is a nuclear receptor that regulates metabolic homeostasis in the liver. Previous studies identified phosphatidylcholines as potential endogenous agonist ligands for LRH‐1. In the liver, distinct subsets of phosphatidylcholine species are generated by two different pathways: choline addition to phosphatidic acid through the Kennedy pathway and trimethylation of phosphatidylethanolamine through phosphatidylethanolamine N‐methyl transferase (PEMT). Approach and Results Here, we report that a PEMT–LRH‐1 pathway specifically couples methyl metabolism and mitochondrial activities in hepatocytes. We show that the loss of Lrh‐1 reduces mitochondrial number, basal respiration, beta‐oxidation, and adenosine triphosphate production in hepatocytes and decreases expression of mitochondrial biogenesis and beta‐oxidation genes. In contrast, activation of LRH‐1 by its phosphatidylcholine agonists exerts opposite effects. While disruption of the Kennedy pathway does not affect the LRH‐1‐mediated regulation of mitochondrial activities, genetic or pharmaceutical inhibition of the PEMT pathway recapitulates the effects of Lrh‐1 knockdown on mitochondria. Furthermore, we show that S‐adenosyl methionine, a cofactor required for PEMT, is sufficient to induce Lrh‐1 transactivation and consequently mitochondrial biogenesis. Conclusions A PEMT–LRH‐1 axis regulates mitochondrial biogenesis and beta‐oxidation in hepatocytes.

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Nuclear‐mitochondrial crosstalk: On the role of the nuclear receptor liver receptor homolog‐1 (NR5A2) in the regulation of mitochondrial metabolism, cell survival, and cancer

Michalek

Brunner

2020

IUBMB Life

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Liver receptor homolog-1 (LRH-1, NR5A2) is an orphan nuclear receptor with widespread activities in the regulation of development, stemness, metabolism, steroidogenesis, and proliferation. Many of the LRH-1-regulated processes target the mitochondria and associated activities. While under physiological conditions, a balanced LRH-1 expression and regulation contribute to the maintenance of a physiological equilibrium, deregulation of LRH-1 has been associated with inflammation and cancer. In this review, we discuss the role and mechanism(s) of how LRH-1 regulates metabolic processes, cell survival, and cancer in a nuclear-mitochondrial crosstalk, and evaluate its potential as a pharmacological target.

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Structure and Dynamics of the Liver Receptor Homolog 1–PGC1α Complex

Cited by 23 publications

References 43 publications

Development of the first low nanomolar Liver Receptor Homolog-1 agonist through structure-guided design

Development of the first low nanomolar Liver Receptor Homolog-1 agonist through structure-guided design

Methyl‐Sensing Nuclear Receptor Liver Receptor Homolog‐1 Regulates Mitochondrial Function in Mouse Hepatocytes

Nuclear‐mitochondrial crosstalk: On the role of the nuclear receptor liver receptor homolog‐1 (NR5A2) in the regulation of mitochondrial metabolism, cell survival, and cancer

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