Structure of the RXR-RAR DNA-binding complex on the retinoic acid response element DR1

Department of Pharmacology, University of Virginia, Charlottesville, VA 22908, USA,.
The EMBO Journal (Impact Factor: 10.75). 04/2000; 19(5):1045-54. DOI: 10.1093/emboj/19.5.1045
Source: PubMed

ABSTRACT The 9-cis retinoic acid receptor (retinoid X receptor, RXR) forms heterodimers with the all-trans retinoic acid receptor (RAR) and other nuclear receptors on DNA regulatory sites composed of tandem binding elements. We describe the 1.70 A resolution structure of the ternary complex of RXR and RAR DNA-binding regions in complex with the retinoic acid response element DR1. The receptors recognize identical half-sites through extensive base-specific contacts; however, RXR binds exclusively to the 3' site to form an asymmetric complex with the reverse polarity of other RXR heterodimers. The subunits associate in a strictly DNA-dependent manner using the T-box of RXR and the Zn-II region of RAR, both of which are reshaped in forming the complex. The protein-DNA contacts, the dimerization interface and the DNA curvature in the RXR-RAR complex are distinct from those of the RXR homodimer, which also binds DR1. Together, these structures illustrate how the nuclear receptor superfamily exploits conformational flexibility and locally induced structures to generate combinatorial transcription factors.

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    • "Consequently, heterodimerization has a three-fold effect: it leads to a novel response element repertoire, increases the efficiency of DNA binding relative to the corresponding homodimers, and allows two signaling inputs, that of the ligands of RXR and its partner. Crystal structures of DBD homo- and heterodimers have defined the surfaces involved in dimerization [9], [10]. It is important to point out that the response element repertoire for receptor homo- and heterodimers is dictated by the DBD while LBDs stabilizes the dimers, but do not contribute to response element selection. "
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    PLoS ONE 12/2013; 8(12):e84569. DOI:10.1371/journal.pone.0084569 · 3.23 Impact Factor
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    • "PPARγ/RXRα without DNA has been shown to be elongated with no interdomain interactions [17]. In complex with idealized DNA, the first atomic resolution structure of integral PPARγ/RXRα obtained by X-ray crystallography [15] confirmed the structural information concerning isolated domains [11] [31] [32] and also revealed an interdomain contact between the LBD of PPARγ and the DBD of RXR [13], although the functional correlation is limited to a single point mutation. The N-terminal domain, unfolded, was not visible in the electron density map. "
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    PPAR Research 12/2012; 2012:701412. DOI:10.1155/2012/701412 · 1.64 Impact Factor
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    • "PPARα transcriptional activity on fatty acid β-oxidation genes requires heterodimeric association with retinoid X receptor (RXR)α. RXRs in response to their ligands, all-trans or 9-cis retinoic acid, bind as RXR/RXR homodimers or RXR/RAR heterodimers to retinoic acid response elements (RAREs) in the promoters of target genes, mediating the biological effects of retinoids in gene activation (Rastinejad et al., 2000). The rhythmic expression and activity of PPARα are influenced by DBP, HLF, and TEF, and in the liver these PAR-bZIP transcription factors contribute to the circadian transcription of genes coding for acyl-coenzyme A (CoA) thioesterases, leading to a cyclic release of fatty acids from thioesters. "
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