4n5g
From Proteopedia
Crystal Structure of RXRa LBD complexed with a synthetic modulator K8012
Structural highlights
Function[RXRA_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 PubMedRetinoid X receptor-alpha (RXRalpha), an intriguing and unique drug target, can serve as an intracellular target mediating the anticancer effects of certain nonsteroidal anti-inflammatory drugs (NSAIDs), including sulindac. We report the synthesis and characterization of two sulindac analogs, K-8008 and K-8012, which exert improved anticancer activities over sulindac in a RXRalpha-dependent manner. The analogs inhibit the interaction of the N-terminally truncated RXRalpha (tRXRalpha) with the p85alpha subunit of PI3K, leading to suppression of AKT activation and induction of apoptosis. Crystal structures of the RXRalpha ligand-binding domain (LBD) with K-8008 or K-8012 reveal that both compounds bind to tetrameric RXRalpha LBD at a site different from the classical ligand-binding pocket. Thus, these results identify K-8008 and K-8012 as tRXRalpha modulators and define a binding mechanism for regulating the nongenomic action of tRXRalpha. Sulindac-Derived RXRalpha Modulators Inhibit Cancer Cell Growth by Binding to a Novel Site.,Chen L, Wang ZG, Aleshin AE, Chen F, Chen J, Jiang F, Alitongbieke G, Zeng Z, Ma Y, Huang M, Zhou H, Cadwell G, Zheng JF, Huang PQ, Liddington RC, Zhang XK, Su Y Chem Biol. 2014 Apr 2. pii: S1074-5521(14)00077-5. doi:, 10.1016/j.chembiol.2014.02.017. PMID:24704507[5] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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