title: Modulation of human nuclear receptor LRH-1 activity by phospholipids and SHP.
abstract: 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.
authors.affiliation: Department of Chemistry, Lineberger Comprehensive Cancer Center, School of Medicine, University of North Carolina at Chapel Hill, 27599, USA.
authors.forename: Eric A
authors.initials: EA
authors.lastname: Ortlund
authors.forename: Yoonkwang
authors.initials: Y
authors.lastname: Lee
authors.forename: Isaac H
authors.initials: IH
authors.lastname: Solomon
authors.forename: Janet M
authors.initials: JM
authors.lastname: Hager
authors.forename: Rachid
authors.initials: R
authors.lastname: Safi
authors.forename: Yunhee
authors.initials: Y
authors.lastname: Choi
authors.forename: Ziqiang
authors.initials: Z
authors.lastname: Guan
authors.forename: Ashutosh
authors.initials: A
authors.lastname: Tripathy
authors.forename: Christian R H
authors.initials: CR
authors.lastname: Raetz
authors.forename: Donald P
authors.initials: DP
authors.lastname: McDonnell
authors.forename: David D
authors.initials: DD
authors.lastname: Moore
authors.forename: Matthew R
authors.initials: MR
authors.lastname: Redinbo
mesh_terms: 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
chemical_list: 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