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PMID:15723037

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Citation

Ortlund, EA, Lee, Y, Solomon, IH, Hager, JM, Safi, R, Choi, Y, Guan, Z, Tripathy, A, Raetz, CR, McDonnell, DP, Moore, DD and Redinbo, MR (2005) Modulation of human nuclear receptor LRH-1 activity by phospholipids and SHP. Nat. Struct. Mol. Biol. 12:357-63

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.

Links

PubMed Online version:10.1038/nsmb910

Keywords

Amino Acid Sequence; Binding Sites; Crystallography, X-Ray; DNA-Binding Proteins/chemistry; DNA-Binding Proteins/genetics; DNA-Binding Proteins/metabolism; Gene Expression Regulation; HeLa Cells; Humans; Models, Molecular; Molecular Sequence Data; Phospholipids/chemistry; Phospholipids/metabolism; Phospholipids/pharmacology; Protein Binding; Protein Structure, Tertiary; Receptors, Cytoplasmic and Nuclear/chemistry; Receptors, Cytoplasmic and Nuclear/genetics; Receptors, Cytoplasmic and Nuclear/metabolism; Sequence Alignment; Spectrometry, Mass, Electrospray Ionization; Transcription Factors

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

HUMAN:NR5A2

involved_in

GO:0006355: regulation of transcription, DNA-templated

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:NR5A2

enables

GO:0005543: phospholipid binding

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

HUMAN:NR5A2

enables

GO:0003700: DNA-binding transcription factor activity

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

See also

References

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