Defining a canonical ligand-binding pocket in the orphan nuclear receptor Nurr1

Abstract

Nuclear receptor related 1 protein (Nurr1/NR4A2) is an orphan nuclear receptor that is considered to function without a canonical ligand-binding pocket. A crystal structure of the Nurr1 ligand-binding domain (LBD) revealed no physical space in the conserved region where other nuclear receptors with solvent accessible apo-protein ligand-binding pockets bind synthetic and natural ligands. Using solution NMR spectroscopy, hydrogen/deuterium exchange mass spectrometry, and molecular dynamics simulations, we show here that the putative canonical ligand-binding pocket in the Nurr1 LBD is dynamic with high solvent accessibility, exchanges between two or more conformations on the microsecond-to-millisecond timescale, and can expand from the collapsed crystalized conformation to allow binding of unsaturated fatty acids. These findings should stimulate future studies to probe the ligandability and druggability of Nurr1 for both endogenous and synthetic ligands, which could lead to new therapeutics for Nurr1-related diseases, including Parkinsons disease and schizophrenia.