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Insights into the binding mode and mechanism of action of some atypical retinoids as ligands of the small heterodimer partner (SHP).

ABSTRACT: The Small Heterodimer Partner (SHP) is an orphan nuclear receptor and an atypical member of the nuclear receptor superfamily Since its discovery, a growing body of evidences have pointed out a pivotal role for SHP in the transcriptional regulation of a variety of target genes involved in diverse metabolic pathways. While we have previously developed a homology model of the structure of SHP that was instrumental to identify a putative ligand binding pocket and suggest the possibility of the development of synthetic modulators, others reported that some atypical retinoids may represent the first synthetic ligands for this receptor. In this work, we report a combined computational approach aimed at shedding further lights on the binding mode and mechanism of action of some atypical retinoids as ligands of SHP. The results have been instrumental to design mutagenesis experiments whose preliminary data suggest the presence of a functional site in SHP as defined by residues Phe96, Arg138 and Arg238. While further experimental studies are ongoing, these findings constitute the basis for the design and identification of novel synthetic modulators of SHP functions.

SUBMITTER: Cellanetti M

PROVIDER: S-EPMC4169293 | biostudies-literature | 2010 Nov

REPOSITORIES: biostudies-literature

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Insights into the binding mode and mechanism of action of some atypical retinoids as ligands of the small heterodimer partner (SHP).

Cellanetti Marco M Gunda Viswanath V Wang Li L Macchiarulo Antonio A Pellicciari Roberto R

Journal of computer-aided molecular design 20100930 11

The Small Heterodimer Partner (SHP) is an orphan nuclear receptor and an atypical member of the nuclear receptor superfamily Since its discovery, a growing body of evidences have pointed out a pivotal role for SHP in the transcriptional regulation of a variety of target genes involved in diverse metabolic pathways. While we have previously developed a homology model of the structure of SHP that was instrumental to identify a putative ligand binding pocket and suggest the possibility of the devel ...[more]

PMID: 20882396

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Project description:1,4-Dioxane (1,4-DX) is an environmental contaminant found in drinking water throughout the United States (US). While it is a suspected liver carcinogen, there is no federal or state maximum contaminant level for 1,4-DX in drinking water. Very little is known about the mechanisms by which this chemical elicits liver carcinogenicity. In the present study, we performed chronic and short-term dosing studies in female BDF-1 mice to explore the toxic effects of 1,4-DX. Histopathology studies and a multi-omics approach (transcriptomics and metabolomics) were performed to investigate potential mechanisms of toxicity. Mice were exposed to various concentrations of 1,4-DX (0, 50, 500 and 5,000 mg/L) in their drinking water for one or four weeks. Immunohistochemical analysis of the liver revealed an increase in the number of H2AXγ-positive hepatocytes (a marker of DNA double strand breaks) in mice exposed to 5,000 mg/L 1,4-DX for one and four weeks. In addition, an expansion of precholangiocytes was observed after four weeks of 5,000 mg/L 1,4-DX exposure, as reflected by CK-7 immunostaining. An increase in these markers reflect both DNA damage and repair mechanisms. Liver transcriptomics profiling showed that exposure to 5,000 mg/L 1,4-DX for four weeks resulted in the differential expression of 65 genes compared to controls. Pathway analysis of the transcriptomic data revealed 1,4-DX-induced perturbations in multiple signaling pathways in the liver, including those involved in xenobiotic metabolism, nicotine degradation and glutathione-mediated detoxification. Changes to these pathways as a result of 1,4-DX exposure reflect would be predicted to impact the oxidative stress response, detoxification, and DNA damage. Liver, kidney, stool and urine metabolomics profiling revealed no effect of 5,000 mg/L 1,4-DX exposure for one or four weeks on metabolites. We speculate that this may be reflective of DNA damage being counterbalanced by the repair response, with the net result being a null overall effect on the systemic biochemistry of the exposed mice. Our results show a novel approach for the investigation of environmental chemicals that do not elicit cell death, but have activated the repair systems in response to 1,4-DX exposure

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Insights into the binding mode and mechanism of action of some atypical retinoids as ligands of the small heterodimer partner (SHP).

Publications

Insights into the binding mode and mechanism of action of some atypical retinoids as ligands of the small heterodimer partner (SHP).

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