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Updated: Apr 7, 2026
Luminescence Resonance Energy Transfer to Study Conformational Changes in Membrane Proteins Expressed in Mammalian Cells
Published on: September 16, 2014
Selective ligand activity at Nur/retinoid X receptor complexes revealed by dimer-specific bioluminescence resonance
Xavier C Giner1, David Cotnoir-White1, Sylvie Mader1
1*Faculté de Pharmacie and Groupe de Recherche Universitaire sur le Médicament, and Institut de Recherche en Immunologie et Cancérologie, Université de Montréal, Montréal, Québec, Canada.
Abstract:
Retinoid X receptors (RXRs) play a role as master regulators because of their capacity to form heterodimers with other nuclear receptors (NRs). Accordingly, retinoid signaling is involved in multiple biologic processes, including development, cell differentiation, metabolism, and cell death. However, the role and function of RXRs in different heterodimer complexes remain unidentified, mainly because most RXR drugs (called rexinoids) are not selective of specific heterodimer complexes. The lack of selectivity strongly limits the use of rexinoids for specific therapeutic approaches. To better characterize rexinoids at specific NR complexes, we have developed and optimized luciferase (Luc) protein complementation(PCA)-based bioluminescence resonance energy transfer (BRET) assays that can directly measure recruitment of a coactivator (CoA) motif fused to yellow fluorescent protein (YFP) by specific NR dimers. To validate the assays, we compared rexinoid modulation of CoA recruitment by the RXR homodimer and by the heterodimers Nur77/RXR and Nurr1/RXR. Results revealed that some rexinoids display selective CoA recruitment activities with homo- or heterodimer complexes. In particular, SR11237 (BMS649) has stronger potency for recruitment of CoA motif and transcriptional activity with the heterodimer Nur77/RXR than other complexes. This technology should be useful in identifying new compounds with specificity for individual dimeric species formed by NRs.
Insights
Retinoid X receptors (RXRs) are key regulators, but their specific functions in different complexes are unclear. New assays reveal selective coactivator recruitment by rexinoids, aiding targeted drug development.
Area of Science:
- Molecular Biology
- Endocrinology
- Pharmacology
Background:
- Retinoid X receptors (RXRs) are crucial nuclear receptors regulating diverse biological processes through heterodimerization.
- The precise roles of RXRs within specific heterodimer complexes are largely unknown due to a lack of selective drugs (rexinoids).
Purpose of the Study:
- To develop and validate novel assays for measuring rexinoid selectivity towards specific RXR-containing nuclear receptor (NR) heterodimers.
- To characterize the coactivator recruitment profiles of rexinoids across different RXR homo- and heterodimers.
Main Methods:
- Utilized luciferase protein complementation (PCA)-based bioluminescence resonance energy transfer (BRET) assays.
- Measured coactivator (CoA) motif recruitment by specific NR dimers in response to rexinoid treatment.
- Validated assays by comparing rexinoid activity on RXR homodimers and Nur77/RXR and Nurr1/RXR heterodimers.
Main Results:
- Demonstrated that certain rexinoids exhibit selective coactivator recruitment for specific RXR homo- or heterodimer complexes.
- Identified SR11237 (BMS649) as a rexinoid with enhanced potency for coactivator recruitment and transcriptional activity with the Nur77/RXR heterodimer.
Conclusions:
- Developed a robust BRET-based assay technology for direct measurement of rexinoid selectivity at specific NR dimer interfaces.
- This technology offers a valuable tool for discovering novel compounds with tailored specificity for individual NR dimeric species, advancing therapeutic applications.
