TY - JOUR
T1 - Identification of a Binding Site for Unsaturated Fatty Acids in the Orphan Nuclear Receptor Nurr1
AU - De Vera, Ian Mitchelle S.
AU - Giri, Pankaj K.
AU - Munoz-Tello, Paola
AU - Brust, Richard
AU - Fuhrmann, Jakob
AU - Matta-Camacho, Edna
AU - Shang, Jinsai
AU - Campbell, Sean
AU - Wilson, Henry D.
AU - Granados, Juan
AU - Gardner, William J.
AU - Creamer, Trevor P.
AU - Solt, Laura A.
AU - Kojetin, Douglas J.
N1 - Publisher Copyright:
© 2016 American Chemical Society.
PY - 2016/7/15
Y1 - 2016/7/15
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84978640692&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84978640692&partnerID=8YFLogxK
U2 - 10.1021/acschembio.6b00037
DO - 10.1021/acschembio.6b00037
M3 - Article
C2 - 27128111
AN - SCOPUS:84978640692
SN - 1554-8929
VL - 11
SP - 1795
EP - 1799
JO - ACS Chemical Biology
JF - ACS Chemical Biology
IS - 7
ER -