Modulation of human nuclear receptor LRH-1 activity by phospholipids and SHP.

Published

Journal Article

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.

Full Text

Duke Authors

Cited Authors

  • Ortlund, EA; Lee, Y; Solomon, IH; Hager, JM; Safi, R; Choi, Y; Guan, Z; Tripathy, A; Raetz, CRH; McDonnell, DP; Moore, DD; Redinbo, MR

Published Date

  • April 2005

Published In

Volume / Issue

  • 12 / 4

Start / End Page

  • 357 - 363

PubMed ID

  • 15723037

Pubmed Central ID

  • 15723037

International Standard Serial Number (ISSN)

  • 1545-9993

Digital Object Identifier (DOI)

  • 10.1038/nsmb910

Language

  • eng

Conference Location

  • United States