Receptors Without Ligands

Abstract

Wang et al. determined the crystal structure at 2.2 Å resolution of the ligand-binding domain (LBD) of Nurr1, an "orphan receptor" with no known ligand, and obtained evidence supporting a regulated but ligand-independent mechanism of Nurr1 function. Nuclear receptor transcription factors (NRs) modulate gene transcription after the binding of small lipophilic ligands. The tertiary structure of the unliganded Nurr1 LBD was similar to that of liganded NR LBDs, indicating a transcriptionally active conformation. In Nurr1, the ligand-binding pocket found in other NRs was obliterated by bulky hydrophobic residues, which suggested a ligand-free model of Nurr1 function. Moreover, structural and mutational analyses showed that Nurr1 lacked a classical coactivator-corepressor binding site and likely associated with coregulators through some alternative domain. The authors used a two-hybrid conditional assembly assay of Nurr1 LBD fragment function in two cell lines with different levels of Nurr1 activity to show that increased assembly of the fragments correlated with increased Nurr1 transcriptional activity. Both Nurr1 transcriptional activity and LBD stabilization were inhibited by expression of a constitutively active mutant of the receptor tyrosine kinase Ret. Nurr1 is a member of a highly conserved subgroup of NRs (the nerve growth factor-induced clone B subfamily); the authors conclude that other members of this family will likely show ligand-free activity as well. They speculate that the data support a previously described hypothesis that ancestral NRs functioned independently of ligand and that ligand binding was acquired independently by several NRs during evolution. Z. Wang, G. Benolt, J. Liu, S. Prasad, P. Aarnisalo, X. Liu, H. Xu, N. P. C. Walker, T. Perlmann, Structure and function of Nurr1 identifies a class of ligand-independent nuclear receptors. Nature 423 , 555-560 (2003). [Online Journal]