Journal
NATURE STRUCTURAL & MOLECULAR BIOLOGY
Volume 12, Issue 4, Pages 357-363Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/nsmb910
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Funding
- NIDDK NIH HHS [DK62229] Funding Source: Medline
- NIGMS NIH HHS [1U54GM069338] Funding Source: Medline
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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 angstrom 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.
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