Identification of the First Retinoid X Receptor Homodimer Antagonist

Koch, Stacie S. Canan; Dardashti, L. J.; Hebert, J. J.; White, Steven K; Croston, Glenn; Flatten, Karen S.; Heyman, Richard A.; Nadzan, Alex M.

doi:10.1021/jm960311d

Cited by 58 publications

(17 citation statements)

References 47 publications

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“…Therefore, UVI3003 which has a longer alkyl group than UVI3002 should similarly prevent H12 associating to the LBD and the RXR complex should adopt an antagonistic conformation as in RXR-LG100754. In agreement with this molecular mechanism of antagonism, analogues of LG100754 with shorter groups such as ethyl or methyl groups instead of the propoxy group act either as partial agonist or full agonist for RXR, respectively [31].…”

Section: Resultsmentioning

confidence: 67%

The “Phantom Effect” of the Rexinoid LG100754: Structural and Functional Insights

et al. 2010

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Retinoic acid receptors (RARs) and Retinoid X nuclear receptors (RXRs) are ligand-dependent transcriptional modulators that execute their biological action through the generation of functional heterodimers. RXR acts as an obligate dimer partner in many signalling pathways, gene regulation by rexinoids depending on the liganded state of the specific heterodimeric partner. To address the question of the effect of rexinoid antagonists on RAR/RXR function, we solved the crystal structure of the heterodimer formed by the ligand binding domain (LBD) of the RARα bound to its natural agonist ligand (all-trans retinoic acid, atRA) and RXRα bound to a rexinoid antagonist (LG100754). We observed that RARα exhibits the canonical agonist conformation and RXRα an antagonist one with the C-terminal H12 flipping out to the solvent. Examination of the protein-LG100754 interactions reveals that its propoxy group sterically prevents the H12 associating with the LBD, without affecting the dimerization or the active conformation of RAR. Although LG100754 has been reported to act as a ‘phantom ligand’ activating RAR in a cellular context, our structural data and biochemical assays demonstrate that LG100754 mediates its effect as a full RXR antagonist. Finally we show that the ‘phantom ligand effect’ of the LG100754 is due to a direct binding of the ligand to RAR that stabilizes coactivator interactions thus accounting for the observed transcriptional activation of RAR/RXR.

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Section: Resultsmentioning

confidence: 67%

The “Phantom Effect” of the Rexinoid LG100754: Structural and Functional Insights

et al. 2010

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“…These investigations identified molecules with agonistic-, partial agonistic-, antagonistic-, and inverse agonistic-activity [21,22,48]. Strikingly, an RXR antagonist, LG100754 (LG754) [49], was previously described as being able to function as an RXR-RARα activator. It was proposed that LG754 binding to RXR does induce a conformational change in the unliganded-RARα LBD and the recruitment of the CoA SRC-1, raising the question of allosteric communications in RXR-RAR heterodimers [50,51].…”

Section: Introductionmentioning

confidence: 99%

Regulation of RXR-RAR Heterodimers by RXR- and RAR-Specific Ligands and Their Combinations

Maire

Teyssier

Balaguer

et al. 2019

Cells

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The three subtypes (α, β, and γ) of the retinoic acid receptor (RAR) are ligand-dependent transcription factors that mediate retinoic acid signaling by forming heterodimers with the retinoid X receptor (RXR). Heterodimers are functional units that bind ligands (retinoids), transcriptional co-regulators and DNA, to regulate gene networks controlling cell growth, differentiation, and death. Using biochemical, crystallographic, and cellular approaches, we have set out to explore the spectrum of possibilities to regulate RXR-RAR heterodimer-dependent transcription through various pharmacological classes of RAR- and RXR- specific ligands, alone or in combination. We reveal the molecular details by which these compounds direct specificity and functionality of RXR-RAR heterodimers. Among these ligands, we have reevaluated and improved the molecular and structural definition of compounds CD2665, Ro41-5253, LE135, or LG100754, highlighting novel functional features of these molecules. Our analysis reveals a model of RXR-RAR heterodimer action in which each subunit retains its intrinsic properties in terms of ligand and co-regulator binding. However, their interplay upon the combined action of RAR- and RXR-ligands allows for the fine tuning of heterodimer activity. It also stresses the importance of accurate ligand characterization to use synthetic selective retinoids appropriately and avoid data misinterpretations.

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“…LG100754 ( 3 ) was reported as the first RXR antagonist in 1996 [42]. Prior to that, in 1994, Boehm et al had noted that some compounds having RXR binding affinity, but not showing RXR agonist activity, might exhibit RXR antagonistic activity [73].…”

Section: Representative Rxr Antagonistsmentioning

confidence: 99%

“…Antagonistic activity of LG100754 ( 3 ), the first reported RXR antagonist, was evaluated in terms of the IC 50 value on transcriptional activation by 2 in reporter gene assays using CV-1 cells [42]. Similarly, PA452 ( 9b ) [48] and UVI3003 ( 11 ) [54] were evaluated using PA024 ( 31 ) and CD3254 ( 33 ) as agonists, respectively.…”

Section: Evaluation Of Rxr Antagonistic Activitymentioning

confidence: 99%

Retinoid X Receptor Antagonists

Watanabe

Kakuta

2018

IJMS

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Retinoid X receptor (RXR) antagonists are not only useful as chemical tools for biological research, but are also candidate drugs for the treatment of various diseases, including diabetes and allergies, although no RXR antagonist has yet been approved for clinical use. In this review, we present a brief overview of RXR structure, function, and target genes, and describe currently available RXR antagonists, their structural classification, and their evaluation, focusing on the latest research.

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Identification of the First Retinoid X Receptor Homodimer Antagonist

Cited by 58 publications

References 47 publications

The “Phantom Effect” of the Rexinoid LG100754: Structural and Functional Insights

The “Phantom Effect” of the Rexinoid LG100754: Structural and Functional Insights

Regulation of RXR-RAR Heterodimers by RXR- and RAR-Specific Ligands and Their Combinations

Retinoid X Receptor Antagonists

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