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Updated: Jul 15, 2026
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Detecting the Ligand-binding Domain Dimerization Activity of Estrogen Receptor Alpha Using the Mammalian Two-Hybrid Assay
Published on: December 19, 2018
Structural plasticity in the oestrogen receptor ligand-binding domain
Kendall W Nettles1, John B Bruning, German Gil
1Department of Cancer Biology, The Scripps Research Institute, 5353 Parkside Drive, Jupiter, Florida 33458, USA. knettles@scripps.edu
EMBO Reports
|May 1, 2007
Summary
The oestrogen receptor alpha (ERalpha) shows structural plasticity, accommodating novel ligands in an extended pocket. This reveals steroid hormone receptors can bind diverse pharmacophores, expanding drug discovery possibilities.
Area of Science:
- Structural biology
- Molecular endocrinology
- Drug discovery
Background:
- Steroid hormone receptors typically bind rigid ligands.
- Nuclear receptors exhibit pocket elasticity for flexible lipid ligands.
- Oestrogen receptor alpha (ERalpha) is a key target in endocrine therapy.
Purpose of the Study:
- To determine the X-ray crystal structure of ERalpha bound to a novel oestradiol derivative.
- To investigate the binding mode and structural implications of this interaction.
- To explore the potential for ERalpha to accommodate a wider range of ligands.
Main Methods:
- X-ray crystallography
- Co-crystallization of oestrogen receptor alpha (ERalpha) with an oestradiol derivative
- Structural analysis of the ligand-binding domain
Main Results:
- The oestradiol derivative with a prosthetic group binds in a novel, extended pocket within the ERalpha ligand-binding domain.
- Unlike bulky antagonists, this ligand is fully enclosed, acting as a potent agonist.
- Demonstrates significant structural plasticity in the ERalpha ligand-binding pocket.
Conclusions:
- Steroid hormone receptors, including ERalpha, possess greater structural adaptability than previously recognized.
- The ERalpha ligand-binding pocket can accommodate diverse pharmacophores through conformational changes.
- This finding broadens the scope for designing novel therapeutic agents targeting steroid hormone receptors.
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