May 29, 2003
Nuclear Cell Receptor Acts On Its Own
Researchers find unique functions for Nurr1, a nuclear receptor implicated in Parkinson’s disease.
Stockholm (May 29)–As a key contact point for regulating gene transcription, nuclear receptors represent an important family of drug targets. But about half of all nuclear receptors are defined as orphan receptors because they lack known ligands, the docking station that relays signals through cells. In a study published in the journal Nature, researchers show that one of these orphan receptors, Nurr1, acts independently from ligands that are part of the same nuclear receptor family.
“An important and controversial question has been if all of these proteins will turn out to have ligands or if they function as transcription factors by other mechanisms,” said study co-author, Dr. Thomas Perlmann of the Ludwig Institute for Cancer Research, Stockholm Branch. “Because Nurr1 lacks a cavity in the domain used by other nuclear receptors for ligand binding, we now have unequivocal proof that it works independent of these ligands.”
Nurr1 has evoked a lot of interest because of its potential importance in Parkinson’s disease. Others studies have shown that Nurr1 is essential for the development of dopamine neurons in mice, and the receptor turns up in inherited cases of Parkinson’s.
Using X-ray crystallography, the research team was able to determine the structure of Nurr1, which led to two unique findings. First, the ligand-binding domains contained no cavity because these were crowded out by bulky hydrophobic residues. Secondly, Nurr1 lacks a classical binding site for co-activators.
Despite these unique features, the ligand binding domains of Nurr1 are still regulated in cells. Interestingly, Dr. Perlmann notes, transcriptional activity improves when Nurr1 binding domains adopt a more stable conformation.
“This study has implications for our understanding of how nuclear receptors have evolved as ligand-binding receptors,” said Dr. Perlmann. “Moreover, the results may help better define how orphan receptors are used as drug targets.”
Abstract
Wang Z, Benoit G, Liu J, Prasad S, Aarnisalo P, Liu X, Xu H, Walker NP, Perlmann T. Structure and function of Nurr1 identifies a class of ligand-independent nuclear receptors. Nature. 2003 May 29;423(6939):555-60