1ZKY: Human Estrogen Receptor Alpha Ligand-Binding Domain In Complex With Obcp-3m And A Glucocorticoid Receptor Interacting Protein 1 Nr Box Ii Peptide

Estrogen receptors alpha (ERalpha) and beta (ERbeta) have distinct functions and differential expression in certain tissues. These differences have stimulated the search for subtype-selective ligands. Therapeutically, such ligands offer the potential to target specific tissues or pathways regulated by one receptor subtype without affecting the other. As reagents, they can be utilized to probe the physiological functions of the ER subtypes to provide information complementary to that obtained from knock-out animals. A fluorescence resonance energy transfer-based assay was used to screen a 10,000-compound chemical library for ER agonists. From the screen, we identified a family of ERbeta-selective agonists whose members contain bulky oxabicyclic scaffolds in place of the planar scaffolds common to most ER ligands. These agonists are 10-50-fold selective for ERbeta in competitive binding assays and up to 60-fold selective in transactivation assays. The weak uterotrophic activity of these ligands in immature rats and their ability to stimulate expression of an ERbeta regulated gene in human U2OS osteosarcoma cells provides more physiological evidence of their ERbeta-selective nature. To provide insight into the molecular mechanisms of their activity and selectivity, we determined the crystal structures of the ERalpha ligand-binding domain (LBD) and a peptide from the glucocorticoid receptor-interacting protein 1 (GRIP1) coactivator complexed with the ligands OBCP-3M, OBCP-2M, and OBCP-1M. These structures illustrate how the bicyclic scaffolds of these ligands are accommodated in the flexible ligand-binding pocket of ER. A comparison of these structures with existing ER structures suggests that the ERbeta selectivity of OBCP ligands can be attributed to a combination of their interactions with Met-336 in ERbeta and Met-421 in ERalpha. These bicyclic ligands show promise as lead compounds that can target ERbeta. In addition, our understanding of the molecular determinants of their subtype selectivity provides a useful starting point for developing other ER modulators belonging to this relatively new structural class.
PDB ID: 1ZKYDownload
MMDB ID: 38954
PDB Deposition Date: 2005/5/4
Updated in MMDB: 2012/11
Experimental Method:
x-ray diffraction
Resolution: 2.25  Å
Source Organism:
synthetic construct
Similar Structures:
Biological Unit for 1ZKY: tetrameric; determined by author and by software (PISA)
Molecular Components in 1ZKY
Label Count Molecule
Proteins (4 molecules)
Estrogen Receptor(Gene symbol: ESR1)
Molecule annotation
Nuclear Receptor Coactivator 2(Gene symbol: NCOA2)
Molecule annotation
Chemicals (2 molecules)
* Click molecule labels to explore molecular sequence information.

Citing MMDB