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Differential modulation of nuclear receptor LRH-1 through targeting buried and surface regions of the binding pocket

ABSTRACT: Differential modulation of nuclear receptor LRH-1 through targeting buried and surface regions of the binding pocket

PROVIDER: PRJNA818205 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR18396455.fastq.gz	Fastqsanger.gz
	SRR18396456.fastq.gz	Fastqsanger.gz
	SRR18396457.fastq.gz	Fastqsanger.gz
	SRR18396458.fastq.gz	Fastqsanger.gz
	SRR18396459.fastq.gz	Fastqsanger.gz

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Differential modulation of nuclear receptor LRH-1 through targeting buried and surface regions of the binding pocket

Project description:Liver receptor homolog-1 (LRH-1) is a phospholipid-sensing nuclear receptor that has shown promise as a target for alleviating intestinal inflammation and disease states characterized by metabolic dysregulation in the liver. LRH-1 contains an unusually large ligand binding pocket but generating synthetic modulators has been challenging. Leveraging a hexahydropentalene (6HP) core, we have had recent success in generating potent and efficacious agonists through two distinct strategies. We targeted residues deep within the pocket to enhance compound binding, while residues at the mouth of the pocket were targeted to mimic interactions made by endogenous phospholipids. Here, we unite these two designs into one hybrid molecule to synthesize the most potent LRH-1 agonist to date. Through a combination of global transcriptomic, biochemical, and structural studies, we show that selective modulation can be driven through contacting deep vs. surface polar regions in the pocket. While deep pocket contacts convey high-affinity, contacts with the pocket mouth dominate allostery and provide a phospholipid-like transcriptional response in cultured cells.

2022-05-10 | GSE199060 | GEO

Selective modulation of nuclear receptor LRH-1 through target-ing buried and surface regions of the binding pocket

Project description:Liver receptor homolog-1 (LRH-1) is a phospholipid-sensing nuclear receptor that has shown promise as a target for alleviat-ing intestinal inflammation and disease states characterized by metabolic dysregulation in the liver. LRH-1 contains an unu-sually large ligand binding pocket, and generating synthetic modulators has been challenging. Leveraging a hexahydropen-talene (6HP) core, we have had recent success in generating potent and efficacious agonists through two distinct strategies. We targeted residues deep within the pocket to enhance compound binding, while residues at the mouth of the pocket were targeted to mimic interactions made by endogenous phospholipids. Here, we unite these two designs into one hybrid mole-cule that is the most potent LRH-1 agonist to date. Through a combination of global transcriptomic, biochemical, and struc-tural studies, we show that selective modulation can be driven through contacting deep vs. surface polar regions in the pock-et. While deep pocket contacts convey high-affinity, contacts with the pocket mouth dominate allostery and provide a phos-pholipid-like transcriptional response in cultured cells.

2022-05-04 | PXD031099 | Pride

Differential Modulation of Nuclear Receptor LRH-1 through Targeting Buried and Surface Regions of the Binding Pocket.

Project description:Liver receptor homologue-1 (LRH-1) is a phospholipid-sensing nuclear receptor that has shown promise as a target for alleviating intestinal inflammation and metabolic dysregulation in the liver. LRH-1 contains a large ligand-binding pocket, but generating synthetic modulators has been challenging. We have had recent success generating potent and efficacious agonists through two distinct strategies. We targeted residues deep within the pocket to enhance compound binding and residues at the mouth of the pocket to mimic interactions made by phospholipids. Here, we unite these two designs into one molecule to synthesize the most potent LRH-1 agonist to date. Through a combination of global transcriptomic, biochemical, and structural studies, we show that selective modulation can be driven through contacting deep versus surface polar regions in the pocket. While deep pocket contacts convey high affinity, contacts with the pocket mouth dominate allostery and provide a phospholipid-like transcriptional response in cultured cells.

| S-EPMC10026694 | biostudies-literature

Global hepatic transcript data from LRH-1 hep+/+ and LRH-1 hep-/- livers

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Project description:Transcript data from LRH-1 WT and LRH-1 K289R livers from mice fed ad libitum and sacrificed at 7 am We used microarrays to detail the global programme of gene expression underlying hepatic function in ad libitum fed mice.

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Global hepatic transcript data from LRH-1 WT and LRH-1 K289R jejunums

Project description:Transcript data from LRH-1 WT and LRH-1 K289R jejunums from mice fed ad libitum and sacrificed at 7 am We used microarrays to detail the global programme of gene expression underlying jejunal function in ad libitum fed mice.

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LRH-1 governs vital transcriptional programs in endocrine sensitive and resistant breast cancer cells: LRH-1 ChIP-seq

Project description:Tumor characteristics are decisive in the determination of treatment strategy for breast cancer patients. Patients with estrogen receptor a(ERa)-positive breast cancer can benefit from long-term hormonal treatment. Nonetheless, the majority of patients will develop resistance to these therapies. Here, we investigated the role of the nuclear receptor liver receptor homolog-1 (LRH-1, NR5A2) in anti-estrogen (AE) sensitive and resistant breast cancer cells. We identified genome-wide LRH-1 binding sites using ChIP-seq, uncovering preferential binding to regions distal to transcriptional start sites (TSS). We further characterized these LRH-1 binding sites by integrating overlapping layers of specific chromatin marks, revealing that many LRH-1 binding sites are active and could be involved in long-range enhancer-promoter looping. Combined with transcriptome analysis of LRH-1 depleted cells, these results show that LRH-1 regulates specific subsets of genes involved in cell proliferation in AE-sensitive and AE-resistant breast cancer cells. Furthermore, the LRH-1 transcriptional program is highly associated with a signature of poor outcome and high-grade breast cancer tumors in vivo. Herein we report the genome-wide location and molecular function of LRH-1 in breast cancer cells and reveal its therapeutic potential for the treatment of breast cancers, notably for tumors resistant to treatments currently used in therapies.

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LRH-1 governs vital transcriptional programs in endocrine sensitive and resistant breast cancer cells: LRH-1 ChIP-seq

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LRH-1 Mitigates Intestinal Inflammatory Disease by Maintaining Epithelial Homeostasis and Cell Survival

Project description:We report the gene expression changes in murine small intestinal organoids following deletion of LRH-1 (NR5A2) and humanization by expression of human LRH-1 in mouse LRH-1 knockout organoids.

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Global hepatic transcript data from LRH-1 hep+/+ and LRH-1 hep-/- livers

Project description:Transcript data from LRH-1 hep+/+ and LRH-1 hep-/- livers from mice fed ad libitum and sacrificed at 7 am We used microarrays to detail the global programme of gene expression underlying hepatic function in ad libitum fed mice. 17-19-week-old mice were fed ad libitum, sacrificed at 7 am, and livers snap-frozen in liquid nitorgen for RNA extraction and hybridization on Affymetrix microarrays.

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