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

ArticleinThe EMBO Journal 19(5):1045-54 · April 2000with11 Reads
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.
    • "This is chiefly as a consequence of variations in the position of their C-terminal AF2 helices, which can mask or expose areas on the LBD surface that are required for cofactor docking (Figure 2(d)). In either the absence of agonist or presence of synthetic antagonists, RXR/RAR heterodimers assemble corepressor complexes by direct Ghyselinck et al., 1997; Rastinejad et al., 2000). Alternate views are shown to highlight the DNA recognition and dimerization functions of the DBD (1DSZ.pdb). "
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    • "It is likely that unobserved pairings are of limited biological utility and consequently are not retained. It is clear that many commonly observed co-operative motif pairings reflect the available motif-binding pockets in the binding partner, for example, docking motifs and modification sites for the same PTM enzyme will often occur in the same protein, increasing the efficiency and specificity of modification [78, 80,103104105106107 . Furthermore , intuitively, motifs with related functionality will be more likely to co-operate (i.e. "
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    • "Sequences that mediate the interaction with the nuclear receptor transcription factors, however, are found as SLiMs, termed co-repressor for nuclear receptor (CoRNR) boxes, embedded within a carboxy-terminal region that lacks significant structural organization1415161718. Type II nuclear receptors, such as the retinoid receptors, bind DNA as heterodimers with a common, RXR partner19202122, and each co-repressor is thought to interact with a nuclear receptor dimer [18,22,23]. To achieve this, NCoR1 uses any two of its three CoRNR boxes to bind directly to the receptors, but only in the absence of the receptor's ligand, such as retinoic acid1415161724,25]. "
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