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Structure and function of Nurr1 identifies a class of ligand-independent nuclear receptors

Abstract

Members of the nuclear receptor (NR) superfamily of transcription factors modulate gene transcription in response to small lipophilic molecules1. Transcriptional activity is regulated by ligands binding to the carboxy-terminal ligand-binding domains (LBDs) of cognate NRs. A subgroup of NRs referred to as ‘orphan receptors’ lack identified ligands, however, raising issues about the function of their LBDs2. Here we report the crystal structure of the LBD of the orphan receptor Nurr1 at 2.2 Å resolution. The Nurr1 LBD adopts a canonical protein fold resembling that of agonist-bound, transcriptionally active LBDs in NRs3, but the structure has two distinctive features. First, the Nurr1 LBD contains no cavity as a result of the tight packing of side chains from several bulky hydrophobic residues in the region normally occupied by ligands. Second, Nurr1 lacks a ‘classical’ binding site for coactivators. Despite these differences, the Nurr1 LBD can be regulated in mammalian cells. Notably, transcriptional activity is correlated with the Nurr1 LBD adopting a more stable conformation. Our findings highlight a unique structural class of NRs and define a model for ligand-independent NR function.

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Figure 1: Ribbon representations of NR LBD structures.
Figure 2: No ligand-binding cavity in Nurr1.
Figure 3: The region of the coactivator-binding site.
Figure 4: The stability of the Nurr1 LBD correlates with cell-specific transcriptional activity.
Figure 5: Receptor tyrosine kinase activated intracellular signalling modulates Nurr1 LBD activity and stability.

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Acknowledgements

We thank P. Cao for MS analysis, J. Lehmann, A. Shiau, B. Shan, C. Ibanez, A. Mata and Ö. Wrange for discussions and advice. This work was supported in part by the Göran Gustafsson Foundation, The European Union Research Training Network and the Swedish Foundation for Strategic Research. The Advanced Light Source at the Lawrence Berkeley National Laboratory is supported by the Director, Office of Science, Office of Basic Sciences, Materials Sciences Division, of the US Department of Energy.

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Correspondence to Nigel P. C. Walker or Thomas Perlmann.

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Wang, Z., Benoit, G., Liu, J. et al. Structure and function of Nurr1 identifies a class of ligand-independent nuclear receptors. Nature 423, 555–560 (2003). https://doi.org/10.1038/nature01645

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