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

Eric A Ortlund1, Yoonkwang Lee, Isaac H Solomon

  • 1Department of Chemistry, Lineberger Comprehensive Cancer Center, School of Medicine, University of North Carolina at Chapel Hill, 27599, USA.

Nature Structural & Molecular Biology
|February 22, 2005
PubMed

Insights

The liver receptor homolog 1 (hLRH-1) binds phospholipids, revealing its mechanism in gene regulation. This finding identifies hLRH-1 as a new target for breast cancer therapies.

Area of Science:

  • Molecular biology
  • Structural biology
  • Biochemistry

Background:

  • The human nuclear receptor liver receptor homolog 1 (hLRH-1) is implicated in breast carcinoma development.
  • hLRH-1 is downregulated by the co-repressor SHP and was considered ligand-independent.

Purpose of the Study:

  • To elucidate the structural basis of hLRH-1 regulation by SHP.
  • To investigate the role of potential ligands in hLRH-1 activity.

Main Methods:

  • X-ray crystallography to determine the structure of hLRH-1 bound to SHP.
  • Mass spectrometry to identify bound ligands.
  • In vivo studies with mutated hLRH-1.

Main Results:

  • The crystal structure revealed SHP's interaction with the AF-2 region of hLRH-1.
  • Electron density indicated phospholipid binding within the hLRH-1 ligand-binding pocket.
  • Mutations in the pocket impaired phospholipid binding and receptor activity.

Conclusions:

  • hLRH-1's gene expression control is mediated by phospholipid binding.
  • hLRH-1 represents a novel therapeutic target for slowing breast cancer progression.

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