The structure of corepressor Dax-1 bound to its target nuclear receptor LRH-1

Department of Biochemistry and Biophysics, University of California, San Francisco, CA 94143, USA.
Proceedings of the National Academy of Sciences (Impact Factor: 9.67). 12/2008; 105(47):18390-5. DOI: 10.1073/pnas.0808936105
Source: PubMed

ABSTRACT The Dax-1 protein is an enigmatic nuclear receptor that lacks an expected DNA binding domain, yet functions as a potent corepressor of nuclear receptors. Here we report the structure of Dax-1 bound to one of its targets, liver receptor homolog 1 (LRH-1). Unexpectedly, Dax-1 binds to LRH-1 using a new module, a repressor helix built from a family conserved sequence motif, PCFXXLP. Mutations in this repressor helix that are linked with human endocrine disorders dissociate the complex and attenuate Dax-1 function. The structure of the Dax-1:LRH-1 complex provides the molecular mechanism for the function of Dax-1 as a potent transcriptional repressor.

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    • "Additionally, DAX1 contains a potent transcriptional repressor domain in its C-terminus [158] [159]. Although there is not yet a protein structure available for human DAX1, the LBD of the mouse homolog has been resolved (PDB ID: 3F5C [160]) and established that the C-terminal domain does not contain a ligand binding site. "
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    ABSTRACT: Nuclear receptors (NRs), a family of 48 transcriptional factors, have been studied intensively for their roles in cancer development and progression. The presence of distinctive ligand binding sites capable of interacting with small molecules has made NRs attractive targets for developing cancer therapeutics. In particular, a number of drugs have been developed over the years to target human androgen- and estrogen receptors for the treatment of prostate cancer and breast cancer. In contrast, orphan nuclear receptors (ONRs), which in many cases lack known biological functions or ligands, are still largely under investigated. This review is a summary on ONRs that have been implicated in prostate and breast cancers, specifically retinoic acid-receptor-related orphan receptors (RORs), liver X receptors (LXRs), chicken ovalbumin upstream promoter transcription factors (COUP-TFs), estrogen related receptors (ERRs), nerve growth factor 1B-like receptors, and "dosage-sensitive sex reversal, adrenal hypoplasia critical region, on chromosome X, gene 1" (DAX1). Discovery and development of small molecules that can bind at various functional sites on these ONRs will help determine their biological functions. In addition, these molecules have the potential to act as prototypes for future drug development. Ultimately, the therapeutic value of targeting the ONRs may go well beyond prostate and breast cancers.
    Cancer Treatment Reviews 10/2014; 40(10). DOI:10.1016/j.ctrv.2014.10.005 · 7.59 Impact Factor
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    • "The primary sequence of TLX LBD comprises amino-acids 187–385. Similar to DAX1 (dosage-sensitive sex reversal, adrenal hypoplasia critical region, on chromosome X, gene 1; NR0B1) [38], SHP (Small Heterodimer partner, NR0B2) [39] and PNR [37], the structural alignment used for designing the TLX LBD model (Fig. 1) revealed that it is shorter than other NR LBDs and lacks the first helices α1 and α2. The alignment also reveals a unique insertion (aa. "
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    ABSTRACT: Nuclear receptors (NRs) are an important group of ligand-dependent transcriptional factors. Presently, no natural or synthetic ligand has been identified for a large group of orphan NRs. Small molecules to target these orphan NRs will provide unique resources for uncovering regulatory systems that impact human health and to modulate these pathways with drugs. The orphan NR tailless (TLX, NR2E1), a transcriptional repressor, is a major player in neurogenesis and Neural Stem Cell (NSC) derived brain tumors. No chemical probes that modulate TLX activity are available, and it is not clear whether TLX is druggable. To assess TLX ligand binding capacity, we created homology models of the TLX ligand binding domain (LBD). Results suggest that TLX belongs to an emerging class of NRs that lack LBD helices α1 and α2 and that it has potential to form a large open ligand binding pocket (LBP). Using a medium throughput screening strategy, we investigated direct binding of 20,000 compounds to purified human TLX protein and verified interactions with a secondary (orthogonal) assay. We then assessed effects of verified binders on TLX activity using luciferase assays. As a result, we report identification of three compounds (ccrp1, ccrp2 and ccrp3) that bind to recombinant TLX protein with affinities in the high nanomolar to low micromolar range and enhance TLX transcriptional repressive activity. We conclude that TLX is druggable and propose that our lead compounds could serve as scaffolds to derive more potent ligands. While our ligands potentiate TLX repressive activity, the question of whether it is possible to develop ligands to de-repress TLX activity remains open.
    PLoS ONE 06/2014; 9(6):e99440. DOI:10.1371/journal.pone.0099440 · 3.23 Impact Factor
    • "Both the residue numbers and the amino acid sequences are based on the PDB entry (mutated residues are presented in italics and missing residues are presented in small letters). (1) 1FM9 chain A (Gampe et al., 2000a), (2) 1PZL (Duda et al., 2004), (3) 1HG4 chain E (Clayton et al., 2001), (4) UniPortKB, (5) 3CJW (Kruse et al., 2008), (6) 3F5C chain B (Sablin et al., 2008), (7) 3P0U chain B (Zhou et al., 2011), (8) 2XHS (Yoo et al., 2011), (9) 1YOW (Krylova et al., 2005), (10) 1PK5 chain A (Sablin et al., 2003), (11) 3ERD chain A (Shiau et al., 1998), (12) 1S9P chain D (Greschik et al., 2004), (13) 1E3G (Matias et al., 2000), (14) 1M2Z chain A (Bledsoe et al., 2002), (15) 1A28 chain B (Williams and Sigler, 1998), (16) 1Y9R chain A (Fagart et al., 2005), (17) 2Q1H (Ortlund et al., 2007), (18) 3RY9 chain B (Carroll et al., 2011), (19) 3GN8 chain A (Bridgham et al., 2009), (20) 2LBD (Renaud et al., 1995), (21) 1BSX chain A (Darimont et al., 1998), (22) 1UHL chain B (Svensson et al., 2003), (23) 1R1 K chain D (Billas et al., 2003), (24) 1RK3 (Vanhooke et al., 2004), (25) 1OSV chain B (Mi et al., 2003), (26) 1NRL chain A (Watkins et al., 2003), (27) 1FM9 chain D (Gampe et al., 2000a), (28) 1NQ7 (Stehlin-Gaon et al., 2003), (29) 1XV9 chain B (Xu et al., 2004), (30) 1OVL chain B (Wang et al., 2003), (31) 1PDU chain A (Baker et al., 2003), (32) 3GYT (Wang et al., 2009), (33) 3N00 (Phelan et al., 2010), (34) 3CQV (Pardee et al., 2009). "
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    ABSTRACT: Structural and sequence alignment analyses have revealed the existence of class-dependent and -independent local motifs involved in the overall fold of the ligand-binding domain (LBD) in the nuclear receptor (NR) superfamily. Of these local motifs, three local motifs, i.e., AF-2 fixed motifs, were involved in the agonist conformation of the activation function-2 (AF-2) region of the LBD. Receptor-agonist interactions increased the stability of these AF-2 fixed motifs in the agonist conformation. In contrast, perturbation of the AF-2 fixed motifs by a ligand or another protein molecule led the AF-2 architecture to adopt an antagonist conformation. Knowledge of this process should provide us with novel insights into the 'agonism' and 'antagonism' of NRs.
    Journal of Structural Biology 12/2013; 185(3). DOI:10.1016/j.jsb.2013.12.007 · 3.23 Impact Factor
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