The orphan nuclear receptor TR4 is a vitamin A-activated nuclear receptor.
Testicular receptors 2 and 4 (TR2/4) constitute a subgroup of orphan nuclear receptors that play important roles in spermatogenesis, lipid and lipoprotein regulation, and the development of the central nervous system. Currently, little is known about the structural features and the ligand regulation of these receptors. Here we report the crystal structure of the ligand-free TR4 ligand binding domain, which reveals an autorepressed conformation. The ligand binding pocket of TR4 is filled by the C-terminal half of helix 10, and the cofactor binding site is occupied by the AF-2 helix, thus preventing ligand-independent activation of the receptor. However, TR4 exhibits constitutive transcriptional activity on multiple promoters, which can be further potentiated by nuclear receptor coactivators. Mutations designed to disrupt cofactor binding, dimerization, or ligand binding substantially reduce the transcriptional activity of this receptor. Importantly, both retinol and retinoic acid are able to promote TR4 to recruit coactivators and to activate a TR4-regulated reporter. These findings demonstrate that TR4 is a ligand-regulated nuclear receptor and suggest that retinoids might have a much wider regulatory role via activation of orphan receptors such as TR4.
Laboratory of Structural Sciences and Drug Discovery, Van Andel Research Institute, Grand Rapids, Michigan 49503, USA. edward.zhou@vai.org
X Edward
XE
Zhou
Kelly M
KM
Suino-Powell
Yong
Y
Xu
Cee-Wah
CW
Chan
Osamu
O
Tanabe
Schoen W
SW
Kruse
Ross
R
Reynolds
James Douglas
JD
Engel
H Eric
HE
Xu
D000818:Animals; D001665:Binding Sites; D019556:COS Cells; D002522:Chlorocebus aethiops; D006801:Humans; D009154:Mutation; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D011987:Receptors, Steroid / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D011988:Receptors, Thyroid Hormone / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D013329:Structure-Activity Relationship; D014801:Vitamin A / Q000737:chemistry* / Q000494:pharmacology; D014815:Vitamins / Q000737:chemistry* / Q000494:pharmacology
C490515:NR2C2 protein, human; D011987:Receptors, Steroid; D011988:Receptors, Thyroid Hormone; D014815:Vitamins; D014801:Vitamin A