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- Title
Modulation of human nuclear receptor LRH-1 activity by phospholipids and SHP.
- Authors
Ortlund, Eric A; Lee, Yoonkwang; Solomon, Isaac H; Hager, Janet M; Safi, Rachid; Choi, Yunhee; Guan, Ziqiang; Tripathy, Ashutosh; Raetz, Christian R H; McDonnell, Donald P; Moore, David D; Redinbo, Matthew R
- 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 1.9Åof 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.
- Subjects
NUCLEAR receptors (Biochemistry); BREAST cancer; TUMOR growth; LIGAND binding (Biochemistry); PHOSPHOLIPIDS; MASS spectrometry
- Publication
Nature Structural & Molecular Biology, 2005, Vol 12, Issue 4, p357
- ISSN
1545-9993
- Publication type
Article
- DOI
10.1038/nsmb910