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Crystal structure of the Retinoic Acid Receptor alpha in complex with compound 24 (JP175)
Structural highlights
FunctionRXRA_HUMAN Receptor for retinoic acid. Retinoic acid receptors bind as heterodimers to their target response elements in response to their ligands, all-trans or 9-cis retinoic acid, and regulate gene expression in various biological processes. The RAR/RXR heterodimers bind to the retinoic acid response elements (RARE) composed of tandem 5'-AGGTCA-3' sites known as DR1-DR5. The high affinity ligand for RXRs is 9-cis retinoic acid. RXRA serves as a common heterodimeric partner for a number of nuclear receptors. The RXR/RAR heterodimers bind to the retinoic acid response elements (RARE) composed of tandem 5'-AGGTCA-3' sites known as DR1-DR5. In the absence of ligand, the RXR-RAR heterodimers associate with a multiprotein complex containing transcription corepressors that induce histone acetylation, chromatin condensation and transcriptional suppression. On ligand binding, the corepressors dissociate from the receptors and associate with the coactivators leading to transcriptional activation. The RXRA/PPARA heterodimer is required for PPARA transcriptional activity on fatty acid oxidation genes such as ACOX1 and the P450 system genes.[1] [2] [3] [4] Publication Abstract from PubMedThe nuclear retinoid X receptors (RXRs) are key ligand sensing transcription factors that serve as universal nuclear receptor heterodimer partners and are thus involved in numerous physiological processes. Therapeutic targeting of RXRs holds high potential but available RXR activators suffer from limited safety. Selectivity for RXR subtypes or for certain RXR heterodimers are promising strategies for safer RXR modulation. Here, we report systematic structure-activity relationship studies on biphenyl carboxylates as new RXR ligand chemotype. We discovered specific structural modifications that enhance potency on RXRs, govern subtype preference, and vary modulation of different RXR heterodimers. Fusion of these structural motifs enabled specific tuning of subtype preferential profiles with markedly improved potency. Our results provide further evidence that RXR subtype selective ligands can be designed and present a novel chemotype of RXR modulators that can be tuned for subtype and heterodimer preferences. A Novel Biphenyl-based Chemotype of Retinoid X Receptor Ligands Enables Subtype and Heterodimer Preferences.,Pollinger J, Schierle S, Gellrich L, Ohrndorf J, Kaiser A, Heitel P, Chaikuad A, Knapp S, Merk D ACS Med Chem Lett. 2019 Aug 16;10(9):1346-1352. doi: , 10.1021/acsmedchemlett.9b00306. eCollection 2019 Sep 12. PMID:31531208[5] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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