title: Identification of a Binding Site for Unsaturated Fatty Acids in the Orphan Nuclear Receptor Nurr1.
abstract: Nurr1/NR4A2 is an orphan nuclear receptor, and currently there are no known natural ligands that bind Nurr1. A recent metabolomics study identified unsaturated fatty acids, including arachidonic acid and docosahexaenoic acid (DHA), that interact with the ligand-binding domain (LBD) of a related orphan receptor, Nur77/NR4A1. However, the binding location and whether these ligands bind other NR4A receptors were not defined. Here, we show that unsaturated fatty acids also interact with the Nurr1 LBD, and solution NMR spectroscopy reveals the binding epitope of DHA at its putative ligand-binding pocket. Biochemical assays reveal that DHA-bound Nurr1 interacts with high affinity with a peptide derived from PIASγ, a protein that interacts with Nurr1 in cellular extracts, and DHA also affects cellular Nurr1 transactivation. This work is the first structural report of a natural ligand binding to a canonical NR4A ligand-binding pocket and indicates a natural ligand can bind and affect Nurr1 function.
authors.forename: Ian Mitchelle S
authors.initials: IM
authors.lastname: de Vera
authors.forename: Pankaj K
authors.initials: PK
authors.lastname: Giri
authors.forename: Paola
authors.initials: P
authors.lastname: Munoz-Tello
authors.forename: Richard
authors.initials: R
authors.lastname: Brust
authors.forename: Jakob
authors.initials: J
authors.lastname: Fuhrmann
authors.forename: Edna
authors.initials: E
authors.lastname: Matta-Camacho
authors.forename: Jinsai
authors.initials: J
authors.lastname: Shang
authors.forename: Sean
authors.initials: S
authors.lastname: Campbell
authors.forename: Henry D
authors.initials: HD
authors.lastname: Wilson
authors.forename: Juan
authors.initials: J
authors.lastname: Granados
authors.forename: William J
authors.initials: WJ
authors.lastname: Gardner
authors.affiliation: Center for Structural Biology, Department of Molecular and Cellular Biochemistry, University of Kentucky , Lexington, Kentucky 40536, United States.
authors.forename: Trevor P
authors.initials: TP
authors.lastname: Creamer
authors.forename: Laura A
authors.initials: LA
authors.lastname: Solt
authors.forename: Douglas J
authors.initials: DJ
authors.lastname: Kojetin
mesh_terms: D001665:Binding Sites; D005231:Fatty Acids, Unsaturated / Q000378:metabolism*; D009682:Magnetic Resonance Spectroscopy; D057126:Nuclear Receptor Subfamily 4, Group A, Member 2 / Q000378:metabolism*
chemical_list: D005231:Fatty Acids, Unsaturated; D057126:Nuclear Receptor Subfamily 4, Group A, Member 2