1xdk
Crystal Structure of the RARbeta/RXRalpha Ligand Binding Domain Heterodimer in Complex with 9-cis Retinoic Acid and a Fragment of the TRAP220 Coactivator
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OverviewOverview
Retinoid receptors (RARs and RXRs) are ligand-activated transcription, factors that regulate the transcription of target genes by recruiting, coregulator complexes at cognate promoters. To understand the effects of, heterodimerization and ligand binding on coactivator recruitment, we, solved the crystal structure of the complex between the RARbeta/RXRalpha, ligand-binding domain heterodimer, its 9-cis retinoic acid ligand, and an, LXXLL-containing peptide (termed NR box 2) derived from the nuclear, receptor interaction domain (NID) of the TRAP220 coactivator. In parallel, we measured the binding affinities of the isolated NR box 2 peptide or the, full-length NID of the coactivator SRC-1 for retinoid receptors in the, presence of various types of ligands. Our correlative analysis of, three-dimensional structures and fluorescence data reveals that, heterodimerization does not significantly alter the structure of, individual subunits or their intrinsic capacity to interact with NR box 2., Similarly, we show that the ability of a protomer to recruit NR box 2 does, not vary as a function of the ligand binding status of the partner, receptor. In contrast, the strength of the overall association between the, heterodimer and the full-length SRC-1 NID is dictated by the combinatorial, action of RAR and RXR ligands, the simultaneous presence of the two, receptor agonists being required for highest binding affinity. We, identified an LXXLL peptide-driven mechanism by which the concerted, reorientation of three phenylalanine side chains generates an "aromatic, clamp" that locks the RXR activation helix H12 in the transcriptionally, active conformation. Finally, we show how variations of helix H11-ligand, interactions can alter the communication pathway linking helices H11, H12, and the connecting loop L11-12 to the coactivator-binding site. Together, our results reveal molecular and structural features that impact on the, ligand-dependent interaction of the RAR/RXR heterodimer with nuclear, receptor coactivators.
About this StructureAbout this Structure
1XDK is a Protein complex structure of sequences from Mus musculus with REA as ligand. Full crystallographic information is available from OCA.
ReferenceReference
Characterization of the interaction between retinoic acid receptor/retinoid X receptor (RAR/RXR) heterodimers and transcriptional coactivators through structural and fluorescence anisotropy studies., Pogenberg V, Guichou JF, Vivat-Hannah V, Kammerer S, Perez E, Germain P, de Lera AR, Gronemeyer H, Royer CA, Bourguet W, J Biol Chem. 2005 Jan 14;280(2):1625-33. Epub 2004 Nov 4. PMID:15528208
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