Modulation of human nuclear receptor LRH-1 activity by phospholipids and SHP.
The human nuclear receptor liver receptor homolog 1 (hLRH-1) plays an important role in the development of breast carcinomas. This orphan receptor is efficiently downregulated by the unusual co-repressor SHP and has been thought to be ligand-independent. We present the crystal structure at a resolution of 1.9 A of the ligand-binding domain of hLRH-1 in complex with the NR box 1 motif of human SHP, which we find contacts the AF-2 region of hLRH-1 using selective structural motifs. Electron density indicates phospholipid bound within the ligand-binding pocket, which we confirm using mass spectrometry of solvent-extracted samples. We further show that pocket mutations reduce phospholipid binding and receptor activity in vivo. Our results indicate that hLRH-1's control of gene expression is mediated by phospholipid binding, and establish hLRH-1 as a novel target for compounds designed to slow breast cancer development.
Ortlund
Eric A
EA
Department of Chemistry, Lineberger Comprehensive Cancer Center, School of Medicine, University of North Carolina at Chapel Hill, 27599, USA.
Lee
Yoonkwang
Y
Solomon
Isaac H
IH
Hager
Janet M
JM
Safi
Rachid
R
Choi
Yunhee
Y
Guan
Ziqiang
Z
Tripathy
Ashutosh
A
Raetz
Christian R H
CR
McDonnell
Donald P
DP
Moore
David D
DD
Redinbo
Matthew R
MR
D000595:Amino Acid Sequence; D001665:Binding Sites; D018360:Crystallography, X-Ray; D004268:DNA-Binding Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation; D006367:HeLa Cells; D006801:Humans; D008958:Models, Molecular; D008969:Molecular Sequence Data; D010743:Phospholipids / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D018160:Receptors, Cytoplasmic and Nuclear / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D016415:Sequence Alignment; D021241:Spectrometry, Mass, Electrospray Ionization; D014157:Transcription Factors
D004268:DNA-Binding Proteins; C082631:NR5A2 protein, human; D010743:Phospholipids; D018160:Receptors, Cytoplasmic and Nuclear; D014157:Transcription Factors; C099713:nuclear receptor subfamily 0, group B, member 2