Structural Basis for Ligand-Independent Activation of the Orphan Nuclear Receptor LRH-1

Sablin, Elena P.; Krylova, I. N.; Fletterick, Robert J.; Ingraham, Holly A.

doi:10.1016/s1097-2765(03)00236-3

Cited by 153 publications

(179 citation statements)

References 54 publications

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“…The structure of the LRH-1͞SHP complex reveals that LRH-1 is folded into the active conformation despite the empty ligand-binding pocket, like the apo LRH-1 structure (10). Based on the apo LRH-1 structure, it was proposed that the coactivator-binding site of LRH-1 is not optimized for binding to LXXLL coregulator motifs (10,18). Contrary to this notion, our quantitative competition experiments reveal that LRH-1 is capable of interacting with a number of coactivator motifs with moderate to high affinity.…”

Section: Discussionmentioning

confidence: 99%

“…The crystal structure of the mouse LRH-1 LBD reveals a sandwich fold of four layers of helices instead of the three layers observed for many other receptors (10). Despite the absence of any ligand in the large ligand-binding pocket, the C-terminal activation helix (AF-2) of LRH-1 is packed in an active conformation.…”

mentioning

confidence: 94%

“…Although the physical regions of SHP that interact with LRH-1 have not been mapped, it is assumed that SHP uses the same LXXLL-related motifs to interact with LRH-1. However, previous structural and mutagenesis studies indicate that the LRH-1 structure is not suitable for optimal binding of an LXXLL coactivator motif (10,18). Thus, the molecular basis for the LRH-1͞SHP interaction remains unclear.…”

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confidence: 99%

“…The structures were determined by molecular replacement by using apo LRH-1 (10) or PPAR␥͞rosiglitazone (20) as a model with the AMORE program (21), and refined with CNS (22).…”

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confidence: 99%

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Structural and biochemical basis for selective repression of the orphan nuclear receptor liver receptor homolog 1 by small heterodimer partner

Choi

Suino

et al. 2005

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

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The functional interaction between the orphan nuclear receptors small heterodimer partner (SHP) and liver receptor homolog 1 (LRH-1), where SHP binds to LRH-1 and represses its constitutive transcriptional activity, is crucial for regulating genes involved in cholesterol homeostasis. Here, we report structural and biochemical analyses of the LRH-1͞SHP interaction. The crystal structure and modeling studies of the LRH-1 ligand-binding domain bound to either of the two LXXLL-related motifs of SHP show that the receptor undergoes conformational changes to accommodate the SHP docking and reveal key residues that determine the potency and selectivity of SHP binding. Through a combination of mutagenesis and binding studies, we demonstrate that only the second SHP LXXLL motif is required for repressing LRH-1, and this motif displays a strong preference for binding to LRH-1 over the closely related receptor steroidogeneic factor 1 (SF-1). Structural comparisons indicate that this binding selectivity is determined by residues flanking the core LXXLL motifs. These results establish a structural model for understanding how SHP interacts with LRH-1 to regulate cholesterol homeostasis and provide new insights into how nuclear receptor͞coregulator selectivity is achieved.steroidogeneic factor 1 ͉ bile acids ͉ coactivators ͉ corepressors L iver receptor homolog 1 (LRH-1, NR5A2) is an orphan nuclear receptor that activates an array of genes responsible for development of endodermal organs such as liver, intestine, and pancreas (reviewed in ref. 1). LRH-1 also plays a central role in lipid homeostasis by regulating genes involved in bile acid synthesis, reverse cholesterol transport, and metabolism of lipoprotein complexes (2-6). In the nuclear receptor superfamily, LRH-1 is most homologous to steroidogeneic factor 1 (SF-1, NR5A1), which is essential for sex differentiation and development of adrenals and gonads (7,8). LRH-1 and SF-1 share a highly conserved DNA-binding domain (DBD, Ͼ90% identity) and a moderately conserved ligand-binding domain (LBD, 56% identity). In contrast to most other nuclear receptors that function as dimers, LRH-1 and SF-1 bind with high affinity as monomers to a conserved consensus DNA site found in the promoters of target genes (9). The high degree of similarity in the DBDs of LRH-1 and SF-1 suggests that their different biological activities are contributed in part by distinct structural features in their LBDs, which recruit specific cofactors to regulate transcription.LRH-1 seems to be a constitutively active transcription factor in that it activates many reporters in the absence of any exogenous ligands. The crystal structure of the mouse LRH-1 LBD reveals a sandwich fold of four layers of helices instead of the three layers observed for many other receptors (10). Despite the absence of any ligand in the large ligand-binding pocket, the C-terminal activation helix (AF-2) of LRH-1 is packed in an active conformation. The constitutive LRH-1 activity is proposed to be the result of the stabilization o...

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 94%

mentioning

confidence: 99%

“…The structures were determined by molecular replacement by using apo LRH-1 (10) or PPAR␥͞rosiglitazone (20) as a model with the AMORE program (21), and refined with CNS (22).…”

mentioning

confidence: 99%

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Structural and biochemical basis for selective repression of the orphan nuclear receptor liver receptor homolog 1 by small heterodimer partner

Choi

Suino

et al. 2005

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

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“…Recent findings demonstrate that LRH-1 has constitutive transcriptional activity by adopting an active conformation with a large but empty ligand pocket (Sablin et al, 2003), but also identify phosphatidyl inositols as ligands modulating LRH-1 transcriptional activity (Krylova et al, 2005).…”

Section: Introductionmentioning

confidence: 99%

The nuclear receptor liver receptor homolog-1 is an estrogen receptor target gene

et al. 2005

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Liver receptor homolog-1 (LRH-1) is a nuclear receptor previously known to have distinct functions during mouse development and essential roles in cholesterol homeostasis. Recently, a new role for LRH-1 has been discovered in tumor progression, giving LRH-1 potential transforming functions. In order to identify critical factors stimulating LRH-1 expression leading to deregulated cellular proliferation, we studied its expression and its regulation in several breast cancer cell lines. We observed that LRH-1 expression was increased in estrogen receptor (ER) a expressing cell lines, whereas weak-to-no expression was found in nonexpressing ERa cell lines. In MCF7, LRH-1 expression was highly induced after treatment with 17b-estradiol (E2). This transcriptional regulation was the result of a direct binding of the ER to the LRH-1 promoter, as demonstrated by gelshift and chromatin immunoprecipitation assays. Interestingly, siRNA-mediated inactivation of LRH-1 decreased the E2-dependent proliferation of MCF7 cells. Finally, LRH-1 protein expression was detected by immunohistochemistry in tumor cells of human mammary ductal carcinomas. Altogether, these data demonstrate that LRH-1 is transcriptionally regulated by the ER a and reinforce the hypothesis that LRH-1 could exert potential oncogenic effects during breast cancer formation.

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Nuclear Receptors, Chemistry of

Campbell

Ingraham

2008

Wiley Encyclopedia of Chemical Biology

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Nuclear hormone receptors are integral players in endocrine networks that lie at the interface between biology and chemistry. Unlike most other classes of transcription factors, these proteins are designed uniquely to bind small molecules and, thus, affect gene expression in response to the cellular and organismal chemical environment. After several decades of research, it is now appreciated that nuclear receptors bind very diverse lipophilic small molecules with a wide range of specificity and affinities. Recent nuclear receptor structures coupled with large‐scale screening efforts challenge the dogma that all nuclear receptors, especially the large subset of constitutively active receptors, will have ligands and will represent tractable drug targets. As such, the “pharmacologic future” for such orphan nuclear receptors may reside outside of the ligand‐binding pocket.

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Structural Basis for Ligand-Independent Activation of the Orphan Nuclear Receptor LRH-1

Cited by 153 publications

References 54 publications

Structural and biochemical basis for selective repression of the orphan nuclear receptor liver receptor homolog 1 by small heterodimer partner

Structural and biochemical basis for selective repression of the orphan nuclear receptor liver receptor homolog 1 by small heterodimer partner

The nuclear receptor liver receptor homolog-1 is an estrogen receptor target gene

Nuclear Receptors, Chemistry of

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